Ahead of print articles
PHENOTYPIC ALTERATIONS IN PERIPHERAL BLOOD B LYMPHOCYTES OF PATIENTS WITH ALZHEIMER\'S DISEASE
Meng-Ting Wang, Ye-Ran Wang, Gui-Hua Zeng, Xiao-Qin Zeng, Zhang-Cheng Fei, Jia Chen, Jin Zhou, Xin-Peng Li, Zhi-Qiang Xu, Yan-Jiang Wang, Yu-Hui Liu
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INTRODUCTION: Dysfunction of humoral immunity has been implicated in the pathogenesis of Alzheimer's disease (AD). The distribution of B lymphocyte subsets and their clinical relevance in AD remain unclear.
OBJECTIVE: In this study, we aimed to investigate the distribution of peripheral blood B lymphocyte subsets and their relevance with cognition and biomarkers in AD.
DESIGN, SETTING, AND PARTICIPANTS: We evaluated the immunophenotype of peripheral B lymphocytes in 27 AD patients confirmed by PET-Amyloid scan and 32 cognitively normal controls.
RESULTS: The phenotype of B lymphocytes is altered in AD patients. AD patients exhibit a decrease in both the numbers and proportions of switched memory (SwM) B cells and double-negative (DN) B cells. The proportion of unswitched memory (USwM) B cells was increased after in vitro stimulation. Additionally, B cells that produce proinflammatory cytokines including GM-CSF, IFN-γ, and TNF-α are increased, while those that produce the anti-inflammatory cytokine IL-10 are decreased in AD patients after in vitro stimulation. These alterations in B cell populations were linked to cognitive functions and biomarkers, including Aβ42/40 and pTau181, in AD patients.
DISCUSSION: This study reveals an altered B-lymphocyte phenotype in AD patients, marked by functional and compositional dysregulation. Further research incorporating mechanistic, longitudinal, and functional studies is needed to determine whether these immune perturbations directly contribute to AD pathogenesis or arise as secondary effects of neurodegeneration.
CITATION:
Meng-Ting Wang ; Ye-Ran Wang ; Gui-Hua Zeng ; Xiao-Qin Zeng ; Zhang-Cheng Fei ; Jia Chen ; Jin Zhou ; Xin-Peng Li ; Zhi-Qiang Xu ; Yan-Jiang Wang ; Yu-Hui Liu (2025): Phenotypic alterations in peripheral blood B Lymphocytes of patients with Alzheimer's Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100135
SAMPLE SIZE ESTIMATES FOR BIOMARKER-BASED OUTCOME MEASURES IN CLINICAL TRIALS IN AUTOSOMAL DOMINANT ALZHEIMER\'S DISEASE
David M Cash, Katy E Morgan, Antoinette O\'Connor, Thomas D Veale, Ian B Malone, Teresa Poole, Tammie LS Benzinger, Brian A Gordon, Laura Ibanez, Yan Li, Jorge J. Llibre-Guerra, Eric McDade, Guoqiao Wang, Jasmeer P Chhatwal, Gregory S Day, Edward Huey, Mathias Jucker, Johannes Levin, Yoshiki Niimi, James M Noble, Jee Hoon Roh, Racquel Sánchez-Valle, Peter R Schofield, Randall J Bateman, Chris Frost, Nick C Fox, The Dominantly Inherited Alzheimer Network (DIAN)
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INTRODUCTION: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.
METHODS: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).
RESULTS: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).
DISCUSSION: Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.
CITATION:
David M Cash ; Katy E Morgan ; Antoinette O'Connor ; Thomas D Veale ; Ian B Malone ; Teresa Poole ; Tammie LS Benzinger ; Brian A Gordon ; Laura Ibanez ; Yan Li ; Jorge J. Llibre-Guerra ; Eric McDade ; Guoqiao Wang ; Jasmeer P Chhatwal ; Gregory S Day ; Edward Huey ; Mathias Jucker ; Johannes Levin ; Yoshiki Niimi ; James M Noble ; Jee Hoon Roh ; Racquel Sánchez-Valle ; Peter R Schofield ; Randall J Bateman ; Chris Frost ; Nick C Fox ; The Dominantly Inherited Alzheimer Network (DIAN) (2025): Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100133
ASSOCIATION OF DIETARY FATTY ACIDS WITH LONGITUDINAL CHANGE IN PLASMA-BASED BIOMARKERS OF ALZHEIMER\'S DISEASE
Serena S. Hoost, Lawrence S. Honig, Min Suk Kang, Aanya Bahl, Annie J. Lee, Danurys Sanchez, Dolly Reyes-Dumeyer, Rafael A. Lantigua, Jeffrey L. Dage, Adam M. Brickman, Jennifer J. Manly, Richard Mayeux, Yian Gu
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BACKGROUND: Elevated intake of omega-3 polyunsaturated fatty acids is linked to a reduced risk of dementia in some prospective studies. However, few studies have examined the relationship between nutrient intake and plasma biomarkers of Alzheimer's disease.
OBJECTIVES: We explored whether omega-3, omega-6, and monounsaturated fat intakes were associated with changes in plasma biomarkers of Alzheimer's disease over time.
DESIGN: The Washington Heights-Inwood Columbia Aging Project is a prospective cohort study (1994–2021); the data set used here includes a mean follow-up of 7.0 years.
SETTING: Community-based in New York City.
PARTICIPANTS: 599 dementia-free individuals at baseline who completed a 61-item food frequency questionnaire and had biomarkers measured in plasma from at least two different time points.
MEASUREMENTS: Fatty acid intake tertiles were computed from participant-completed 61-item Willett semi-quantitative food frequency questionnaires (Channing Laboratory, Cambridge, Massachusetts) obtained once at their baseline visit. Plasma-based biomarker assays were performed, using the single molecule array technology Quanterix Simoa HD-X platform, at baseline and follow-up visits. Generalized Estimating Equations (GEE) models were used to evaluate the association between baseline nutrient intake tertile and changes in biomarkers including phospho-tau181, amyloid-beta 42/40 ratio, phospho-tau181/amyloid-beta42 ratio, glial fibrillary acidic protein, neurofilament light chain, and two biomarker patterns derived from Principal Component Analysis (PCA1 and PCA2), with higher scores indicating a high level of neurodegeneration and low level of Alzheimer's disease burden, respectively). Models were adjusted for age, sex, race/ethnicity, education, and calculated total energy intake initially, and additionally for cerebrovascular risk factors.
RESULTS: Higher baseline omega-3 intake tertile was associated with lesser decline in PCA2 (β = 0.221, p < 0.001) and amyloid-beta 42/40 ratio (β = 0.022, p = 0.003), and a lesser rise in phospho-tau181 (β = -0.037, p = 0.001). Higher omega-6 intake tertile was linked to a lesser rise in phospho-tau181 (β = -0.050, p < 0.001) and glial fibrillary acidic protein (β = -0.028, p = 0.002). Most associations persisted after adjusting for cardiovascular risk factors.
CONCLUSIONS: Higher relative baseline intake of omega-3 and omega-6 fatty acids is associated with lesser progression of blood-based biomarkers of Alzheimer's disease. Consuming healthy fatty acids may help prevent accumulation of Alzheimer's disease-related pathological changes.
CITATION:
Serena S. Hoost ; Lawrence S. Honig ; Min Suk Kang ; Aanya Bahl ; Annie J. Lee ; Danurys Sanchez ; Dolly Reyes-Dumeyer ; Rafael A. Lantigua ; Jeffrey L. Dage ; Adam M. Brickman ; Jennifer J. Manly ; Richard Mayeux ; Yian Gu (2025): Association of dietary fatty acids with longitudinal change in plasma-based biomarkers of Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100117
BRAIN HEALTH PRO/SANTE CERVEAU PRO: THE DEVELOPMENT OF A WEB-BASED PROGRAM FOR DEMENTIA LITERACY AND RISK FACTOR REDUCTION
Sylvie Belleville, Nicole D. Anderson, Louis Bherer, Richard Camicioli, Julie Carrier, Senny Chan, Marc Cuesta, Thien Thanh Dang-Vu, Emily Dwosh, Alexandra J. Fiocco, Guylaine Ferland, Brigitte Gilbert, Elaine Harris, Inbal Itzhak, Pamela Jarrett, Mohamed Abdelhafid Kadri, Danielle Laurin, Teresa Liu-Ambrose, Chris A. McGibbon, Laura Middleton, Lesley Miller, Haakon B. Nygaard, Manuel Montero-Odasso, Kelly Murphy, Natalie Phillips, M. Kathleen Pichora-Fuller, Julie M. Robillard, Eric E. Smith, Mark Speechley, Amal Trigui, Walter Wittich, Howard Chertkow, Howard H. Feldman
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BACKGROUND: Online educational programs focused on ways to improve brain health could increase participant literacy, empowerment, and engagement in activities that support personal brain health, potentially reducing dementia risk.
OBJECTIVES: Our goal was to develop an evidence-based online educational program with a focus on risk and protective factors for dementia. Here we present the rationale and features of the program and include results from a pilot study that assessed usability and acceptability.
DESIGN: This project is part of the Can-Thumbs UP (CTU) initiative. An Intervention Mapping Approach framework and co-construction approach was used to develop the online program. A pre-post pilot open label design was used to test the usability and acceptance of this at-home educational program.
SETTING: The program and assessment for the pilot study were delivered fully remotely.
PARTICIPANTS: Twenty community-dwelling older adults (60–83 years of age, 65 % female) living in Canada who were at increased risk of dementia.
PROGRAM: The Brain Health PRO/Santé Cerveau PRO is a web-based 45-week program available in French and English. It provides general information and guidance on seven modifiable risk factors for dementia: physical activity, nutrition, cognitively stimulating activities, sleep, social and psychological health, vascular health, and vision/hearing. After completing a brief intake questionnaire, users are provided with an individualized risk profile to personalize priorities and goals. During the course of the program, users receive feedback on lifestyle changes. For this pilot study, participants completed a 15-week version of the program.
MEASUREMENTS: This pilot study reports measures of usability (System Usability Scale), acceptance (Technology Acceptance Model-2) as well as risk profiles at intake based on self-reported questionnaires.
RESULTS: Two logic models were developed to identify the determinants of risk for dementia and how these could be targeted by the program. A review of dementia risk and protective factors and online educational programs for older adults, as well as co-creation activities with experts, stakeholders, and citizen advisors, were used to identify the determinants, target, format, and content of the program. The pilot study reports excellent usability and acceptance with scores of 80.4/100 and 93.5/120 respectively.
CONCLUSION: Intervention mapping and co-construction approaches facilitated the design of a program that effectively balances the delivery of scientific content with the specific constraints, needs and abilities of older adults.
CITATION:
Sylvie Belleville ; Nicole D. Anderson ; Louis Bherer ; Richard Camicioli ; Julie Carrier ; Senny Chan ; Marc Cuesta ; Thien Thanh Dang-Vu ; Emily Dwosh ; Alexandra J. Fiocco ; Guylaine Ferland ; Brigitte Gilbert ; Elaine Harris ; Inbal Itzhak ; Pamela Jarrett ; Mohamed Abdelhafid Kadri ; Danielle Laurin ; Teresa Liu-Ambrose ; Chris A. McGibbon ; Laura Middleton ; Lesley Miller ; Haakon B. Nygaard ; Manuel Montero-Odasso ; Kelly Murphy ; Natalie Phillips ; M. Kathleen Pichora-Fuller ; Julie M. Robillard ; Eric E. Smith ; Mark Speechley ; Amal Trigui ; Walter Wittich ; Howard Chertkow ; Howard H. Feldman ; the CTU expert group for the Canadian Consortium on Neurodegeneration in Aging (CCNA), CAN-THUMBS UP Study Group (2025): Brain health PRO/Santé cerveau PRO: The development of a web-based program for dementia literacy and risk factor reduction. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100134
PATIENT MANAGEMENT PATHWAYS IN DEMENTIA – RESOURCE UTILISATION, DIAGNOSIS AND DRUG TREATMENT IN THE STOCKHOLM REGION, SWEDEN
Emil Aho, Dorota Religa, Mozhu Ding, Bengt Winblad, Linus Jönsson, Karin Modig
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BACKGROUND: New diagnostic and therapeutic options for Alzheimer's disease are beginning to be introduced and expected igto become more widely available in the coming years. Improved understanding of current pathways in diagnosis and initial care of patients with dementia can help inform choices around how best to integrate new technologies in existing care structures.
OBJECTIVES: The aim of this study is to describe the care management pathways defined by the involvement of specialist and primary care for individuals with newly diagnosed dementia. It also seeks to characterise individuals in different management pathways based on resource use prior to diagnosis, the type of dementia diagnosis received, and the proportion who receive symptomatic anti-dementia drug treatment.
DESIGN: Observational cohort study.
SETTING: Stockholm region, Sweden.
PARTICIPANTS: All newly diagnosed dementia cases between 1st January 2018 to 30th June 2020 (n = 9,781). Dementia diagnoses in primary care were based on Regional Stockholm health care database and diagnoses in specialist care were based on the National Patient Register in Sweden.
MEASUREMENTS: Care management pathways were categorized into three groups: primary care only (diagnosed and followed up in primary care), specialist, no follow-up (diagnosed in specialist care but not followed up in specialist care), and specialist with follow-up (diagnosed and followed up in specialist care). These classifications were based on patients’ care episodes from the date of diagnosis and the subsequent 18 months. age at diagnosis, resource utilisation one-year prior diagnosis and diagnosis given and symptomatic anti-dementia treatment 18 months after initial diagnosis.
RESULTS: A total of 9,781 newly diagnosed dementia cases were identified. In the 18 months following diagnosis, 63 % of patients were diagnosed either partly or fully in specialist care, while 37 % were diagnosed solely in primary care. Patients diagnosed and managed only in primary care were older, spent more days in hospital, and received more social care in the year preceding their diagnosis. Their total care costs were also the highest. Alzheimer's disease was the most common diagnosis (48 %), while 27 % had an unspecified dementia diagnosis, varying by care setting (61 % for patients managed in primary care only and 6 % for patients diagnosed and followed up in specialist care). Overall, 47 % of patients received symptomatic anti-dementia treatment, with the highest share for patients diagnosed and followed up in specialist care (73 %) and the lowest in primary care only (19 %). Diagnosis varied by age and care setting Alzheimer's was most common in settings involving specialist care, whereas unspecified dementia was more common in primary care only regardless of age.
CONCLUSION: The findings that patients managed exclusively in primary care were older, had higher pre-diagnosis resource utilisation, and were less likely to receive specific diagnoses or anti-dementia treatments highlight the crucial role of primary care in diagnosing and managing dementia among older individuals with complex needs. Further research is needed to explore primary care's role in diagnosis and treatment across diverse healthcare systems.
Future research is needed to explore whether and how new diagnostic tools and treatment for AD could facilitate timely diagnosis and care for older individuals with dementia in primary care.
CITATION:
Emil Aho ; Dorota Religa ; Mozhu Ding ; Bengt Winblad ; Linus Jönsson ; Karin Modig (2025): Patient management pathways in dementia – Resource utilisation, diagnosis and drug treatment in the Stockholm region, Sweden. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100132
LIFESTYLE FACTORS AND PLASMA BIOMARKERS OF ALZHEIMER\'S DISEASE: A NARRATIVE REVIEW
Claudie Hooper, Nicola Coley, Julien Delrieu, Sophie Guyonnet
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Alzheimer's disease (AD) is a neurodegenerative disorder characterised by amyloid-β (Aβ), tau hyperphosphorylation and neurodegeneration. Blood-based biomarkers are emerging as a minimally invasive tool for disease detection and monitoring. This review depicts the relationships between modifiable lifestyle factors (nutrition, physical activity (PA), sleep, alcohol consumption, smoking, and social isolation) and plasma biomarkers of AD: Aβ42, Aβ40, Aβ42/40, phosphorylated tau, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein. Limited evidence suggests that better nutrition is associated with favourable AD plasma biomarker profiles and that PA is associated with less plasma NfL and Aβ, whilst poor sleep is associated with elevated plasma Aβ. However, lack of data and inconsistent findings highlight the need for further investigation to substantiate or refute these trends. Moreover, future research should include the analysis of lifestyle on plasma biomarkers according to gender, metabolic health and APOE status. Considering the growing emphasis on modifiable lifestyle factors for preventing and delaying dementia onset further investigation is justified.
CITATION:
Claudie Hooper ; Nicola Coley ; Julien Delrieu ; Sophie Guyonnet (2025): Lifestyle factors and plasma biomarkers of Alzheimer's disease: A narrative review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100130
MULTI-OMICS ANALYSIS OF DRUGGABLE GENES TO FACILITATE ALZHEIMER\'S DISEASE THERAPY: A MULTI-COHORT MACHINE LEARNING STUDY
Jichang Hu, Yong Luo, Xiaochuan Wang
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BACKGROUND: The swift rise in the prevalence of Alzheimer's disease (AD) alongside its significant societal and economic impact has created a pressing demand for effective interventions and treatments. However, there are no available treatments that can modify the progression of the disease.
METHODS: Eight AD brain tissues datasets and three blood datasets were obtained. Consensus clustering was utilized as a method to discern the various subtypes of AD. Then, module genes were screened using weighted correlation network analysis (WGCNA). Furthermore, screening hub genes was conducted through machine-learning analyses. Finally, A comprehensive analysis using a systematic approach to druggable genome-wide Mendelian randomization (MR) was conducted.
RESULTS: Two AD subclasses were identified, namely cluster.A and cluster.B. The levels of gamma secretase activity, beta secretase activity, and amyloid-beta 42 were found to be significantly elevated in patients classified within cluster A when compared to those in cluster B. Furthermore, by utilizing the differentially expressed genes shared among these clusters, along with identifying druggable genes and applying WGCNA to these subtypes, we were able to develop a scoring system referred to as DG.score. This scoring system has demonstrated remarkable predictive capability for AD when evaluated against multiple datasets. Besides, A total of 30 distinct genes that may serve as potential drug targets for AD were identified across at least one of the datasets investigated, whether derived from brain samples or blood analyses. Among the identified genes, three specific candidates that are considered druggable (LIMK2, MAPK8, and NDUFV2) demonstrated significant expression levels in both blood and brain tissues. Furthermore, our research also revealed a potential association between the levels of LIMK2 and concentrations of CSF Aβ (OR 1.526 (1.155–2.018)), CSF p-tau (OR 1.106 (1.024–01.196)), and hippocampal size (OR 0.831 (0.702–0.948)).
CONCLUSIONS: This study provides a notable advancement to the existing literature by offering genetic evidence that underscores the potential therapeutic advantages of focusing on the druggable gene LIMK2 in the treatment of AD. This insight not only contributes to our understanding of AD but also guides future drug discovery efforts.
CITATION:
Jichang Hu ; Yong Luo ; Xiaochuan Wang (2025): Multi-omics analysis of druggable genes to facilitate Alzheimer's disease therapy: A multi-cohort machine learning study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100128
DIETARY PATTERNS AND BLOOD-BASED BIOMARKERS OF ALZHEIMER\'S DISEASE IN COGNITIVELY INTACT OLDER ADULTS: FINDINGS FROM A POPULATION-BASED STUDY
Anja Mrhar, Adrián Carballo-Casla, Giulia Grande, Martina Valletta, Claudia Fredolini, Laura Fratiglioni, Milica Gregori? Kramberger, Aleš Kuhar, Bengt Winblad, Amaia Calderón-Larrañaga, Davide Liborio Vetrano
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BACKGROUND: Diet can impact cognitive aging, but comprehensive data from human studies is lacking and the underlying biological mechanisms are still not fully understood.
OBJECTIVES: To investigate the associations between two dietary patterns consistently linked to inflammation and brain health [the Mediterranean diet (MDS) and inflammatory potential of diet (EDII)] and five blood-based biomarkers of Alzheimer´s disease (AD) in a sample of dementia-free community-dwelling older adults.
DESIGN AND SETTING: We used cross-sectional data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K).
PARTICIPANTS: Participants who were institutionalized, had dementia or Parkinson's disease, or had missing data on diet and/or biomarkers were excluded. Our study sample consisted of 1907 adults ≥60 years old.
MEASUREMENTS: Adherence to the MDS and EDII was assessed using a validated food frequency questionnaire. T-tau, p-tau181, Aβ 42/40, NfL, and GFAP were measured in serum. Associations were estimated through quantile regression models at the 25th, 50th, and 75th percentiles of the biomarkers’ levels, and were adjusted for potential confounders and stratified by sex, age, and APOE-e4 genotype.
RESULTS: In the whole sample, higher adherence to the MDS was associated with lower levels of p-tau181 at the 50th and 75th percentiles [β (95% CI) per 1-SD increment = -0.028 (-0.053, -0.002) and -0.036 (-0.072, -0.001), respectively], while higher adherence to the EDII was associated with higher levels of NfL at the 75th percentile [β (95% CI) per 1-SD increment =0.031 (0.008, 0.053)]. Associations with other biomarkers were only apparent at lower levels of their distribution. Subgroup analyses showed: 1) a stronger inverse association between the MDS and p-tau181 in APOE-e4 carriers than non-carriers, and 2) an inverse association of the MDS with GFAP only in participants ≥78 years.
CONCLUSIONS: Diet seems to be associated with biomarkers of AD pathology in cognitively intact older adults. Some associations were more apparent in the presence of genetic predisposition for AD or advanced age.
CITATION:
Anja Mrhar ; Adrián Carballo-Casla ; Giulia Grande ; Martina Valletta ; Claudia Fredolini ; Laura Fratiglioni ; Milica Gregorič Kramberger ; Aleš Kuhar ; Bengt Winblad ; Amaia Calderón-Larrañaga ; Davide Liborio Vetrano (2025): Dietary patterns and blood-based biomarkers of Alzheimer's disease in cognitively intact older adults: Findings from a population-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100124
REPLY TO THE LETTER TO THE EDITOR: ENHANCING STATIN RESEARCH FOR ALZHEIMER\'S PREVENTION: SUGGESTIONS FOR FUTURE STUDIES AND POLICY IMPLICATIONS
Zirong Ye, Jiahe Deng, Xiuxia Wu, Jingwen Cai, Sicheng Li, Xiaochun Chen, Jiawei Xin
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CITATION:
Zirong Ye ; Jiahe Deng ; Xiuxia Wu ; Jingwen Cai ; Sicheng Li ; Xiaochun Chen ; Jiawei Xin (2025): Reply to the letter to the Editor: Enhancing Statin Research for Alzheimer's Prevention: Suggestions for Future Studies and Policy Implications. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100119
LETTER TO THE EDITOR: ENHANCING STATIN RESEARCH FOR ALZHEIMER\'S PREVENTION: SUGGESTIONS FOR FUTURE STUDIES AND POLICY IMPLICATIONS
Yumei Zhong, Shanshan Liu, Xiaofeng Lv
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CITATION:
Yumei Zhong ; Shanshan Liu ; Xiaofeng Lv (2025): Letter to the Editor: Enhancing statin research for Alzheimer's prevention: Suggestions for future studies and policy implications. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100118
CURRENT STATUS AND FUTURE DIRECTIONS FOR THE DIAGNOSIS AND MANAGEMENT OF MILD COGNITIVE IMPAIRMENT IN SOUTHEAST ASIA: A SEACURE CONSENSUS PAPER
Gursimar Bhalla, Pricilia Tanoto, Ashwati Vipin, Xiao Yuan James Chen, Yi Jin Leow, Christopher Chen, Philip Lin Kiat Yap, Reshma A Merchant, Saima Hilal, Anam Paulus Ong, Encarnita Raya Ampil, Mohamad Imran Idris, Irene Looi, Jacqueline Dominguez, Suraya Yusoff, Maw Pin Tan, Cong Thang Tran, Mai Trang Tong, Vorapun Senanarong, Yuda Turana, Nagaendran Kandiah
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Global aging populations are facing increased prevalence of mild cognitive impairment (MCI) – the preclinical stage of dementia characterized by single/multi-domain neurocognitive decline that does not impair an individual's normal daily functioning. Asian populations are at increased risk of developing MCI and dementia, and many cases go undetected in Southeast Asia (SEA), resulting in increased burden on patients, caregivers and national healthcare systems. There is an urgent need for efficient and scalable diagnostic and management strategies across SEA. Our findings illustrate that current strategies are limited by insufficient resources and a lack of awareness, particularly in developing SEA nations. Strategies for improving the MCI landscape in SEA include increasing widespread community awareness and cognitive health screenings for individuals with a history of vascular risk factors, validation of traditional cognitive screening tests in the respective countries, greater access to blood-biomarker testing, and the development and validation of novel digitized diagnostics.
CITATION:
Gursimar Bhalla ; Pricilia Tanoto ; Ashwati Vipin ; Xiao Yuan James Chen ; Yi Jin Leow ; Christopher Chen ; Philip Lin Kiat Yap ; Reshma A Merchant ; Saima Hilal ; Anam Paulus Ong ; Encarnita Raya Ampil ; Mohamad Imran Idris ; Irene Looi ; Jacqueline Dominguez ; Suraya Yusoff ; Maw Pin Tan ; Cong Thang Tran ; Mai Trang Tong ; Vorapun Senanarong ; Yuda Turana ; Nagaendran Kandiah (2025): Current status and future directions for the diagnosis and management of mild cognitive impairment in Southeast Asia: A SEACURE consensus paper. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100110
BRAIN HEALTH SERVICES FOR THE SECONDARY PREVENTION OF COGNITIVE IMPAIRMENT AND DEMENTIA: OPPORTUNITIES, CHALLENGES, AND THE BUSINESS CASE FOR EXISTING AND FUTURE FACILITIES
Giovanni B. Frisoni, Federica Ribaldi, Gilles Allali, Théophile Bieth, Andrea Brioschi Guevara, Stefano Cappa, Lisa Cipolotti, Kristian Steen Frederiksen, Jean Georges, Frank Jessen, Giacomo Koch, Hugh Masters, Augusto J. Mendes, Lutz Frölich, Valentina Garibotto, Oriol Grau-Rivera, Federico E. Pozzi, Dorota Religa, Ayda Rostamzadeh, Lenny Shallcross, Susan D. Shenkin, Wiesje M. van der Flier, Meike W. Vernooij, Leonie N.C. Visser, Jeffrey L. Cummings, Philip Scheltens, Bruno Dubois, Elena Moro, Claudio L.A. Bassetti, Miia Kivipelto
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A European Task Force has recently developed and published the concept and protocols for the setup of the innovative health offer of Brain Health Services for the secondary prevention of dementia and cognitive impairment (dBHS). dBHS are outpatient health care facilities where adult persons can find an assessment of their risk of developing cognitive impairment and dementia, have their risk level and contributing factors communicated using appropriate language supported by adequate communication tools, can decide to participate to programs for personalized risk reduction if at higher risk, and benefit from cognitive enhancement interventions. This health offer is distinct from that of currently active memory clinics. The ultimate aim of dBHS is to extend healthy life, free from cognitive impairment. Here, we (i) discuss the pertinent opportunities and challenges for those persons who want to benefit from dBHS, professionals, and wider society, (ii) describe the concepts, protocols, organizational features, and patient journeys of some currently active dBHS in Europe, and (iii) argue in favor of the business case for dBHS in Europe.
CITATION:
Giovanni B. Frisoni ; Federica Ribaldi ; Gilles Allali ; Théophile Bieth ; Andrea Brioschi Guevara ; Stefano Cappa ; Lisa Cipolotti ; Kristian Steen Frederiksen ; Jean Georges ; Frank Jessen ; Giacomo Koch ; Hugh Masters ; Augusto J. Mendes ; Lutz Frölich ; Valentina Garibotto ; Oriol Grau-Rivera ; Federico E. Pozzi ; Dorota Religa ; Ayda Rostamzadeh ; Lenny Shallcross ; Susan D. Shenkin ; Wiesje M. van der Flier ; Meike W. Vernooij ; Leonie N.C. Visser ; Jeffrey L. Cummings ; Philip Scheltens ; Bruno Dubois ; Elena Moro ; Claudio L.A. Bassetti ; Miia Kivipelto (2025): Brain health services for the secondary prevention of cognitive impairment and dementia: Opportunities, challenges, and the business case for existing and future facilities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100098
OPPOSITE CAUSAL EFFECTS OF TYPE 2 DIABETES AND METFORMIN ON ALZHEIMER\'S DISEASE
Dongming Liu, Hongbao Cao, Ancha Baranova, Chenxin Xu, Fuquan Zhang
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BACKGROUND: Type 2 diabetes (T2D) is commonly co-morbid with Alzheimer's disease (AD). However, it remains unclear whether T2D itself or the antidiabetic drug metformin contributes to the progression of AD.
OBJECTIVE: This study aimed to investigate the overall and independent effects of T2D and metformin use on the risk of AD.
METHODS: Summary genome-wide association study datasets were utilized for the Mendelian randomization (MR) and multivariable MR (MVMR) analyses, including ones for T2D (N = 455,017), metformin (N = 456,276), and AD (N = 453,733). Additionally, using the proportional imbalance method, we analyzed AD-related adverse drug events in the FDA Adverse Event Reporting System (FAERS) database (covering Q1 2004 to Q2 2024).
RESULTS: Our two-sample MR analysis indicated that T2D is not associated with the risk of AD (OR: 1.03, CI: 0.99–1.08, P = 0.128). However, while not statistically significant, genetic signature for metformin exposure demonstrated a trend toward an increased risk of AD (OR: 1.05, CI: 1.00–1.09, P = 0.053). Interestingly, in MVMR analysis, which evaluates independent effects of T2D and metformin exposure on T2D, we found a robust association of T2D with a decrease in the risk of AD (OR: 0.82, CI: 0.68–0.98, P = 0.031), while the use of metformin was associated with a higher risk of AD (OR: 1.26, CI: 1.06–1.50, P = 9.45E-3). In the FAERS database, a total of 228,283 metformin-related adverse event reports from 67,742 cases were found. For metformin as the target drug and AD as the target adverse event, signal analysis reported 29 cases of AD (ROR: 0.83, 95 % CI: 0.58–1.19, P = 0.3126).
CONCLUSIONS: Our study reveals the opposite independent causal effects of T2D and metformin exposure on AD. These findings highlight the importance of assessing AD risk when prescribing metformin to patients with T2D.
CITATION:
Dongming Liu ; Hongbao Cao ; Ancha Baranova ; Chenxin Xu ; Fuquan Zhang (2025): Opposite causal effects of type 2 diabetes and metformin on Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100129
LONGITUDINAL ASSOCIATIONS OF CAROTID ARTERY STIFFNESS WITH PROGRESSION OF CEREBROVASCULAR DISEASE, INCIDENT DEMENTIA AND COGNITIVE DECLINE IN OLDER ADULTS
Caroline Robert, Lieng-Hsi Ling, Eugene S.J. Tan, Narayanaswamy Venketasubramanian, Shir Lynn Lim, Lingli Gong, Josephine Lunaria Berboso, Arthur Mark Richards, Christopher Chen, Saima Hilal, Josephine Lunaria Berboso, Arthur Mark Richards, Christopher Chen, Saima Hilal
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BACKGROUND: Carotid artery stiffness is associated with cerebrovascular disease (CeVD) and cognitive impairment, but evidence for its longitudinal effects on progression of CeVD and cognitive decline are limited.
OBJECTIVES: To evaluate the longitudinal associations of carotid artery stiffness with CeVD progression, incident dementia, and cognitive decline.
DESIGN: Longitudinal analyses from a memory-clinic cohort with a follow-up of 2 years.
SETTING: A memory-clinic study.
PARTICIPANTS: 194 participants (mean age=80, 63 % female) with or without cognitive impairments provided consent to take part in the study.
MEASUREMENTS: Participants underwent carotid ultrasonography, brain MRI, and neuropsychological assessments were at baseline and follow-up. Carotid stiffness measures included ß-index, elastic modulus (Ep), and pulse wave velocity-ß (PWV-ß). CeVD markers included white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs) and cortical infarcts. Cognition was assessed with a neuropsychological battery.
RESULTS: After 2 years, incident CeVD cases included lacunes (15.7 %), CMBs (23.8 %), and cortical infarcts (7.6 %). ß-index (ß=0.78, p < 0.001), Ep (ß=0.94, p < 0.001), and PWV-ß (ß=0.15, p = 0.003) were independently associated with WMH progression. Ep (ß=-0.15, p = 0.007) and PWV-ß (ß=-3.68, p = 0.007) were independently associated with visuomotor speed decline. No association was found with incident lacunes, CMBs or dementia.
CONCLUSION: Carotid stiffness progression is associated with WMH progression and visuomotor speed decline.
CITATION:
Caroline Robert ; Lieng-Hsi Ling ; Eugene S.J. Tan ; Narayanaswamy Venketasubramanian ; Shir Lynn Lim ; Lingli Gong ; Josephine Lunaria Berboso ; Arthur Mark Richards ; Christopher Chen ; Saima Hilal (2025): Longitudinal associations of carotid artery stiffness with progression of cerebrovascular disease, incident dementia and cognitive decline in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100127
DISTINCT TRAJECTORIES OF SUBJECTIVE COGNITIVE DECLINE BEFORE DIAGNOSIS OF NEUROCOGNITIVE DISORDERS: LONGITUDINAL MODELLING OVER 18 YEARS
Tau Ming Liew, Tau Ming Liew
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BACKGROUND: Subjective cognitive decline (SCD) is an established predictor of neurocognitive disorders (NCD) (i.e. mild cognitive impairment and dementia). Yet, its construct remains contentious. Many individuals with SCD do not progress to NCD, leading to an alternative term in the literature – ‘functional cognitive disorders’ – to describe the SCD experience in these individuals.
OBJECTIVES: To examine the distinct differences in trajectories of SCD between those who did and did not eventually develop NCD.
DESIGN: Case-control study.
SETTING: Alzheimer's Disease Centers across USA.
PARTICIPANTS: A total of 5,167 participants aged ≥50 years were followed up near-annually to evaluate for SCD and NCD (median follow-up=8.1 years; range=1.0–18.0). Cases were defined as those who developed incident NCD during follow-up; controls completed ≥10 years of follow-up and had normal cognition throughout follow-up period.
MEASUREMENTS: SCD was evaluated with a yes/no question based on “perceived decline in memory relative to previously attained abilities”. The trajectories of SCD were modelled with mixed-effect logistic regression, using a backward timescale.
RESULTS: Those who developed NCD (cases) had new onset of SCD within past 20 years, which became particularly noticeable 13–14 years before diagnosis, and became even more evident in the last 4 years. Those who did not develop NCD (controls) reported SCD since younger age, with the probability of SCD remaining constant over time. The distinctive trajectories were consistent across Alzheimer's and non-Alzheimer's disease, and among those with higher baseline rates of SCD due to psychiatric conditions.
CONCLUSIONS: SCD exhibits distinctive trajectories among those who do and do not progress to NCD. These distinctive trajectories can inform NCD risk for early interventions, and guide public health messaging to distinguish high-risk SCD from normal ageing. Future SCD scales may possibly need to evaluate symptom changes over a longer, 20-year horizon to better capture the new onset of SCD within this longer timeframe.
CITATION:
Tau Ming Liew (2025): Distinct trajectories of subjective cognitive decline before diagnosis of neurocognitive disorders: Longitudinal modelling over 18 years. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100123
REPLY TO THE LETTER TO THE EDITOR: MITOCHONDRIAL DYSFUNCTION AS THE MISSING LINK BETWEEN CIRCADIAN SYNDROME AND DEMENTIA
Linling Yu, Xiong Wang
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CITATION:
Linling Yu ; Xiong Wang (2025): Reply to the Letter to the Editor: Mitochondrial dysfunction as the missing link between circadian syndrome and dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100126
LETTER TO THE EDITOR: MITOCHONDRIAL DYSFUNCTION AS THE MISSING LINK BETWEEN CIRCADIAN SYNDROME AND DEMENTIA
Yu-Hsiang Lin, Kuo-Jen Lin, Po-Ting Lin
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CITATION:
Yu-Hsiang Lin ; Kuo-Jen Lin ; Po-Ting Lin (2025): Letter to the Editor: Mitochondrial dysfunction as the missing link between circadian syndrome and dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100125
THE DISEASE BURDEN, RISK FACTORS AND FUTURE PREDICTIONS OF ALZHEIMER\'S DISEASE AND OTHER TYPES OF DEMENTIA IN ASIA FROM 1990 TO 2021
Jinxuan Guo, Pin Wang, Jin Gong, Wenxian Sun, Xiaodong Han, Chang Xu, Aidi Shan, Xin Wang, Heya Luan, Shaoqi Li, Ruina Li, Boye Wen, Runqi Chen, Sirong Lv, Cuibai Wei
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BACKGROUND: There is a lack of analysis and prediction of the disease burden of Alzheimer's disease and other dementias (ADOD) in Asia.
OBJECTIVES: This study aims to explore the impact of ADOD on the Asian region during the period from 1990 to 2021.
DESIGN: Data on ADOD in Asia from 1990 to 2021 were collected from the Global Burden of Disease (GBD) Study 2021. We analyzed the number and age-standardized rates (ASRs) of incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) of ADOD from 1990 to 2021. Joinpoint regression analysis was performed, and the average annual percent changes (AAPCs) were calculated to evaluate the trends during this period. Subsequently, an auto - regressive integrated moving average (ARIMA) prediction model analysis was conducted to assess the trends in the next 30 years, aiming to report the epidemiology and disease burden of ADOD in Asia.
RESULTS: According to the analysis of the GBD database in 2021, the deaths, DALYs, incidence, and prevalence of ADOD increased by 297.34 %, 249.54 %, 244.73 %, and 250.44 % in Asia from 1990 to 2021. The ASRs of incidence, prevalence, death, and DALYs in both males and females, which consistently increased over the study period, showed that the ASRs of all females were consistently higher than those of males in Asia from 1990 to 2021. During the period from 1990 to 2021, Qatar and the United Arab Emirates witnessed the greatest changes in the number of DALYs, incidence, and prevalence. Afghanistan and China had the highest age-standardized mortality rate (ASMR) in 2021. It is worth noting that high fasting blood glucose is the top risk factor for the onset of ADOD. Females are more susceptible to the risk factor of high body-mass index (BMI), while males are more likely to be affected by smoking. According to the analysis of the ARIMA prediction model, the disease burden of ADOD in Asia will continue to show an upward trend in the next 30 years.
CONCLUSIONS: We should pay attention to the issue of population aging, attach importance to the intervention measures targeting the risk factors of ADOD, and formulate action plans to address the rising incidence of ADOD.
CITATION:
Jinxuan Guo ; Pin Wang ; Jin Gong ; Wenxian Sun ; Xiaodong Han ; Chang Xu ; Aidi Shan ; Xin Wang ; Heya Luan ; Shaoqi Li ; Ruina Li ; Boye Wen ; Runqi Chen ; Sirong Lv ; Cuibai Wei (2025): The disease burden, risk factors and future predictions of Alzheimer's disease and other types of dementia in Asia from 1990 to 2021. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100122
MACHINE LEARNING TO DETECT ALZHEIMER\'S DISEASE WITH DATA ON DRUGS AND DIAGNOSES
Johanna Wallensten, Caroline Wachtler, Nenad Bogdanovic, Anna Olofsson, Miia Kivipelto, Linus Jönsson, Predrag Petrovic, Axel C. Carlsson
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BACKGROUND: Integrating machine learning with medical records offers potential for early detection of Alzheimer's disease (AD), enabling timely interventions.
OBJECTIVES: This study aimed to evaluate the effectiveness of machine learning in constructing a predictive model for AD, designed to predict AD with data up to three years before diagnosis. Using clinical data, including prior diagnoses and medical treatments, we sought to enhance sensitivity and specificity in diagnostic procedures. A second aim was to identify the most important factors in the machine learning models, as these may be important predictors of AD.
DESIGN: The study employed Stochastic Gradient Boosting, a machine learning method, to identify diagnoses predictive of AD using primary healthcare data. The analyses were stratified by sex and age groups.
SETTING: The study included individuals within Region Stockholm, Sweden, using medical records from 2010 to 2022.
PARTICIPANTS: The study analyzed clinical data for individuals over the age of 40. Patients with an AD diagnosis (ICD-10-SE codes F00 or G30) during 2010–2012 were excluded to ensure prospective modeling. In total, AD was identified in 3,407 patients aged 41–69 years and 25,796 patients aged over 69.
MEASUREMENTS: The machine learning model ranked predictive diagnoses, with performance assessed by the area under the receiver operating characteristic curve (AUC). Known and novel predictors were evaluated for their contribution to AD risk.
RESULTS: AUC values ranged from 0.748 (women aged 41–69) to 0.816 (women over 69), with men across age groups falling within this range.
Sensitivity and specificity ranged from 0.73 to 0.79 and 0.66 to 0.79, respectively, across age and gender groups. Negative predictive values were consistently high (≥0.954), while positive predictive values were lower (0.199–0.351).
Additionally, we confirmed known risk factors as predictors and identified novel predictors that warrant further investigation. Key predictors included medical observations, cognitive symptoms, antidepressant treatment, visit frequency, and vitamin B12/folic acid treatment.
CONCLUSIONS: Machine learning applied to clinical data shows promise in predicting AD, with robust model performance across age and sex groups. The findings confirmed known risk factors, such as depression and vitamin B12 deficiency, while also identifying novel predictors that may guide future research. Clinically, this approach could enhance early detection and risk stratification, facilitating timely interventions and improving patient outcomes.
CITATION:
Johanna Wallensten ; Caroline Wachtler ; Nenad Bogdanovic ; Anna Olofsson ; Miia Kivipelto ; Linus Jönsson ; Predrag Petrovic ; Axel C. Carlsson (2025): Machine learning to detect Alzheimer's disease with data on drugs and diagnoses. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100115
CARDIOVASCULAR-KIDNEY-METABOLIC SYNDROME AND INCIDENCE OF DEMENTIA AMONG OLDER ADULTS
Xiaqing Jiang, Amber L. Bahorik, Christina S. Dintica, Kristine Yaffe
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BACKGROUND: Cardiovascular-Kidney-Metabolic Syndrome (CKM) has profound impacts on cardiovascular events and mortality, yet its association with dementia risk remains poorly understood.
OBJECTIVES: To investigate associations between CKM and dementia risk.
DESIGN: The prospective cohort study is within the Health, Aging, and Body Composition study, which enrolled participants from 1997 to 1998, with a 15-year follow-up for incident dementia.
SETTING: The population-based study took place in two US communities in Memphis, Tennessee, and Pittsburgh, Pennsylvania.
PARTICIPANTS: Of the 3,075 participants aged 70 to 79 years initially enrolled, 14 were excluded for lacking baseline cognitive assessment, 308 for baseline cognitive impairment, 4 for missing follow-up, and 108 for missing CKM data, resulting in 2,641 in the analysis.
MEASUREMENTS: CKM staging, as defined recently by the American Heart Association framework, was based on constructs comprising dysfunctional adiposity, metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease (CVD). Dementia was identified using hospital records, prescriptions for dementia medication, and a test of global cognition. Adjusted Cox and Fine-Gray proportional hazards models were used to estimate dementia risk and account for competing risk of death.
RESULTS: The 2,641 participants had a mean (SD) age of 74 (2.8) years at baseline; 53 % were female, 36 % were of Black race, and had a range of baseline CKM: 3 % Stage 0 (no CKM), 4 % Stage 1 (excess/dysfunctional adiposity), 26 % Stage 2 (metabolic risk factors), 24 % Stage 3 (subclinical CVD and CKD), and 43 % Stage 4 (clinical CVD and CKD). Compared to participants with CKM Stages 0–2, those with CKM Stages 3–4 had a 50 % increase in dementia risk (hazard ratio 1.50, 95 % CI 1.20 to 1.86) in the fully adjusted model. The association remained significant after additional adjustment for metabolic risk factors, CVD, and CKD, both separately and together. Accounting for competing risk of death yielded similar results.
CONCLUSIONS: Among community-dwelling older adults, advanced CKM is associated with an increased risk of dementia. Older adults with CKM may need to be followed closely for adverse cognitive outcomes, and modifiable risk factors should be managed proactively.
CITATION:
Xiaqing Jiang ; Amber L. Bahorik ; Christina S. Dintica ; Kristine Yaffe (2025): Cardiovascular-kidney-metabolic syndrome and incidence of dementia among older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100112
QUALITATIVE RESEARCH AND LITERATURE REVIEW SUPPORT THE INTEGRATED ALZHEIMER\'S DISEASE RATING SCALE (IADRS) CONTENT VALIDITY IN EARLY SYMPTOMATIC AD
Laure Delbecque, Emma Elliott, Sophie Cleanthous, Phoebe Heinrich, Stefan Cano, Alette M. Wessels, Alexandra S. Atkins
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BACKGROUND AND OBJECTIVES: The integrated Alzheimer's Disease Rating Scale (iADRS) is a measure of cognition and daily function used to evaluate treatment effects in Alzheimer's disease (AD) clinical trials. This study aimed to assess the content validity of the iADRS in early symptomatic AD, and to determine whether integrating assessment of cognition and function into a single measure of global disease severity is supported by the patients’ experience.
METHODS: A targeted literature review of qualitative research in AD and qualitative interviews with 25 care partners of individuals with early symptomatic AD were conducted. Interviews started with open-ended concept elicitation exploring the patient experience of AD from the care partner perspective, including how cognitive changes affect daily functioning. This was followed by cognitive debriefing of the ADCS-iADL items. Interview transcripts were analyzed thematically. Concepts extracted from the literature review and interviews were categorized into a conceptual model of patient experience of AD. A concept-to-item mapping exercise was conducted to assess the conceptual coverage of the iADRS.
RESULTS: The literature review comprised sixty articles. Interviews were conducted with care partners of 7 individuals with Mild Cognitive Impairment (MCI)-AD and care partners of 18 individuals with dementia due to AD. The resulting conceptual model incorporated 75 concepts related to AD experience categorized into three overarching domains: Cognition, Daily Function and Other Symptoms/Impacts. Interview findings endorsed the close link between cognition and daily function. Concept-to-item mapping demonstrated all Cognition and Daily function sub-domains within the model were assessed by at least one iADRS item, except Work/Professional, providing supportive evidence that the iADRS covers concepts that reflect the patient experience of early symptomatic AD.
CONCLUSIONS: This study offers a comprehensive conceptualisation of the patient experience of early symptomatic AD and highlights the intrinsic connection between cognition and daily function. The findings endorse the relevance of an integrated assessment of cognition and function and provide strong evidence for the content validity of the iADRS, highlighting its utility as a meaningful clinical outcome assessment (COA) for use as an endpoint in AD.
CITATION:
Laure Delbecque ; Emma Elliott ; Sophie Cleanthous ; Phoebe Heinrich ; Stefan Cano ; Alette M. Wessels ; Alexandra S. Atkins (2025): Qualitative research and literature review support the integrated Alzheimer's Disease Rating Scale (iADRS) content validity in early symptomatic AD. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100101
HEALTHY DIETARY PATTERNS IN RELATION TO COGNITIVE PERFORMANCE AND ALZHEIMER\'S DISEASE MORTALITY
Yiying Gong, Hui Chen, Yuxuan Gu, Jie Shen, Ting Shen, Yihong Ding, Mengxi Lu, Liyan Huang, Minqing Yan, Peige Song, Yajie Zhu, Shuang Rong, Changzheng Yuan
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BACKGROUND: Dietary factors play a major role in cognitive aging, but few studies have assessed and compared the associations between specific dietary patterns and Alzheimer's disease (AD) mortality.
METHODS: We included 27,773 U.S. participants (mean age = 59.8 years, 51.4 % female) from the National Health and Nutrition Examination Survey (NHANES) between 1998 and 2016, with follow-up for AD mortality until December 2019. Five dietary pattern scores were calculated utilizing one (1999–2002) or two repeated (2003–2016) 24hr dietary recalls, including the Healthy Eating Index (HEI-2015), the healthful plant-based diet index (hPDI), the alternate Mediterranean diet (aMED), the Dietary Approach to Stop Hypertension diet (DASH), and the Mediterranean-DASH Intervention for Neurodegeneration Delay diet (MIND) scores. We utilized Cox proportional hazard models to evaluate the associations of these dietary pattern scores with AD mortality.
RESULTS: A total of 260 AD deaths occurred during a median follow-up of 9.8 years. Higher aMED score was associated with a lower risk of AD mortality (HRT3 vs T1: 0.72, 95 % CI, 0.52–1.00, p-trend = 0.041). In a sub-sample of 2,713 participants in NHANES 2011-2014, 432 individuals had prevalent psychometric mild cognitive impairment (p-MCI). Higher aMED, MIND, HEI-2015, and hPDI were associated with lower odds of p-MCI. The potential contributors to these associations included higher intake levels of vegetables and nuts, moderate alcohol consumption, and lower intake level of sweets.
CONCLUSIONS: The Mediterranean dietary pattern was associated with more favorable cognitive outcomes among middle-aged and older adults, underscoring the importance of a healthy diet for long-term benefits in cognitive and brain health.
CITATION:
Yiying Gong ; Hui Chen ; Yuxuan Gu ; Jie Shen ; Ting Shen ; Yihong Ding ; Mengxi Lu ; Liyan Huang ; Minqing Yan ; Peige Song ; Yajie Zhu ; Shuang Rong ; Changzheng Yuan (2025): Healthy dietary patterns in relation to cognitive performance and Alzheimer's disease mortality. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100100
COMPARATIVE EFFICACY AND SAFETY OF ANTIDIABETIC AGENTS IN ALZHEIMER\'S DISEASE: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Zixin Cai, Jiaxin Zhong, Guanghui Zhu, Jingjing Zhang
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BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Emerging evidence suggests that antidiabetic agents may offer neuroprotective effects by targeting shared pathophysiological mechanisms such as insulin resistance and neuroinflammation. However, the comparative efficacy, and safety of these agents in the treatment of AD remain unclear.
OBJECTIVES: This study aimed to systematically evaluate and compare the efficacy and safety of antidiabetic agents for improving cognitive outcomes, reducing amyloid-β (Aβ) deposition, and managing adverse effects in patients with AD, using a network meta-analysis of randomized controlled trials (RCTs).
METHODS: A comprehensive literature search was conducted across multiple databases to identify RCTs examining the effects of antidiabetic agents in patients with AD. The primary outcomes included cognitive performance (e.g., MMSE scores), Aβ deposition (measured via CSF biomarkers), and safety/adverse effects. A network meta-analysis was performed to integrate direct and indirect evidence, ranking interventions using Surface Under the Cumulative Ranking (SUCRA) probabilities. Risk of bias was assessed using the Cochrane risk-of-bias tool.
RESULTS: A total of 26 studies, involving 7,361 participants, were included in the analysis. The interventions evaluated included insulin detemir (both low-dose and high-dose), liraglutide, exenatide, metformin, and pioglitazone. Both low-dose insulin detemir (mean difference: 2.10, 95 % CI: 1.04 to 3.15), high-dose insulin detemir (mean difference: 1.40, 95 % CI: -0.07 to 2.88), exenatide (mean difference: 1.19, 95 % CI: 0.06 to 2.32), and metformin combined with exenatide (mean difference: 1.06, 95 % CI: -1.68 to 3.80) showed cognitive improvements compared to placebo. Among these, low-dose insulin detemir demonstrated the most significant improvement. In terms of reducing Aβ deposition, metformin ranked highest in effectiveness, with the highest SUCRA score (84.6), followed by high-dose insulin detemir (SUCRA: 54.1). Low-dose insulin detemir (SUCRA: 51.1) also demonstrated moderate efficacy. Low-dose insulin detemir showed some reduction in Aβ deposition (mean difference: -0.31, 95 % CI: -2.82 to 2.20), although statistical significance was limited. Liraglutide exhibited the highest rate of study treatment withdrawal (mean difference: 1.97, 95 % CI: -0.07 to 4.00), while pioglitazone demonstrated the lowest withdrawal rates (mean difference: 0.07, 95 % CI: -0.03 to 0.17).
CONCLUSIONS: This network meta-analysis provides valuable insights into the comparative efficacy and safety of antidiabetic agents in AD. Low-dose insulin detemir demonstrated the most significant cognitive improvement and a moderate effect on reducing Aβ deposition. Metformin emerged as the most effective agent for reducing Aβ levels, though its effects on cognitive function were less pronounced. Safety profiles varied, with liraglutide associated with the highest rate of treatment withdrawals, while pioglitazone demonstrated the lowest incidence of treatment-related discontinuations. These findings support the potential use of antidiabetic agents, particularly insulin detemir, as a therapeutic option for AD, although further studies are needed to confirm their long-term benefits and safety.
CITATION:
Zixin Cai ; Jiaxin Zhong ; Guanghui Zhu ; Jingjing Zhang (2025): Comparative efficacy and safety of antidiabetic agents in Alzheimer's disease: A network meta-analysis of randomized controlled trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100111
PATIENT ELIGIBILITY FOR AMYLOID-TARGETING IMMUNOTHERAPIES IN ALZHEIMER\'S DISEASE
Jurij Rosen, Frank Jessen
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BACKGROUND: Amyloid beta (Aβ) targeting immunotherapies have evolved as promising treatment options for patients with early symptomatic Alzheimer's disease (AD). Understanding how eligibilty criteria impact on the number of patients potentially qualifying for treatment is of high relevance for designing diagnostic workflows in clinical practice and for estimating required ressources and costs.
OBJECTIVES: We aimed at estimating the number of potentially eligible patients for treatment with the Aβ targeting antibodies aducanumab, lecanemab and donanemab in a specialized center real-world sample by the applying the phase 3 clinical trial and the appropriate use recommendations (AUR) inclusion and exclusion criteria to the data set. The post-mortem report was used for defining amyloid positivity and the presence of AD pathology in this study.
DESIGN: Retrospective, descriptive study.
SETTING: The multicenter National Alzheimer‘s Coordinating Center-Uniform Data Set (NACC-UDS) and Neuropathology Data Set (NACCsingle bondNP).
PARTICIPANTS: We included all 3,343 participants of the NACC dataset with available post-mortem pathology reports.
MEASUREMENTS/RESULTS: 887 participants were potential candidates for anti-Aβ immunotherapy as they presented with amnestic mild cognitive impairment or mild dementia and the clinical diagnosis of AD (amnestic AD syndrome). Applying the criterion of amyloid positivity (post mortem report) and the clinical trial inclusion and exclusion criteria to this sample resulted in 83 (9 %), 275 (31 %), and 172 (19 %) participants eligible for treatment with aducanumab, lecanemab, and donanemab, respectively. Applying the criteria of the AUR resulted in 242 (27 %) and 266 (30 %) participants eligible for treatment with aducanumab or lecanemab, respectively. The eligible participant groups for each antibody showed partial, but not full overlap. Co-pathologies were common.
CONCLUSIONS: The number of eligible participants varies between the different antibodies and the selected groups only partly overlap, indicating partly different groups of eligible participants for each antibody. Since not all inclusion and exclusion criteria can be extracted from the NACC-UDS dataset, the real number of eligible patients will be smaller.
CITATION:
Jurij Rosen ; Frank Jessen (2025): Patient eligibility for amyloid-targeting immunotherapies in Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100102
FEASIBILITY AND ACCEPTABILITY OF REMOTE APOE-GENOTYPING AMONG RESEARCH VOLUNTEERS OF AN ONLINE RECRUITMENT REGISTRY (THE DUTCH BRAIN RESEARCH REGISTRY)
L. Waterink, S.J. van der Lee, D. Nijland, F.I. van der Zee, L.N.C. Visser, Y.A.L. Pijnenburg, S.A.M. Sikkes, W.M. van der Flier, M.D. Zwan
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BACKGROUND: Participant recruitment for preclinical Alzheimer's disease (AD) prevention studies is challenging. Online registries facilitate large scale prescreening of individuals at risk for AD to accelerate recruitment. APOE-prescreening has the potential to better identify at-risk individuals. This study investigated the feasibility and acceptability of at-home APOE-genotyping in cognitively-normal registrants of an online registry.
METHODS: We invited 9,287 cognitively-normal registrants of Dutch Brain Research Registry (DBRR) aged 50 to 75 for at-home APOE-genotype testing, without receiving the results. Feasibility was measured by participation ratio (participation/interested), swab-return ratio (returned-swabs/participation), and genotyping-success ratio (analyzed swabs/returned swabs). Acceptability was measured with online questions about information provision and project scope. We explored prescreening questions potentially reducing screen-failures.
RESULTS: Feasibility was high with an 0.89 participation ratio (2,886/3,251), 0.90 swab-return ratio (2,886/2,597), 0.99 genotyping-success ratio (2,558/2,597). Acceptability was high, as participants were content with the information provision (87 %-97 %, n = 1,709–1,894), which was also well understood (91 %-93 %, n = 1,772–1,802). Among successful-analyzed swabs (n = 2,558), 27 % participants were APOE-ε4 heterozygote (n = 703), and 2 % homozygote (n = 60). Prescreening on a positive family history leads to a third reduction in the number of invitations needed to identify one APOE-ε4 carrier.
CONCLUSION: Our results suggest that APOE-ɛ4 genotyping in participants of an online research registry is feasible, well received and could be used to prescreen individuals at risk for AD for prevention studies. Adding a positive family history before invitation for APOE-genotyping, would further improve the prescreening process and reduce screen failures when identifying carriers.
CITATION:
L. Waterink ; S.J. van der Lee ; D. Nijland ; F.I. van der Zee ; L.N.C. Visser ; Y.A.L. Pijnenburg ; S.A.M. Sikkes ; W.M. van der Flier ; M.D. Zwan ; (2025): Feasibility and acceptability of remote APOE-genotyping among research volunteers of an online recruitment registry (The Dutch Brain Research Registry). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100099
INTEGRATIVE SINGLE-CELL RNA SEQUENCING AND MENDELIAN RANDOMIZATION ANALYSIS REVEAL THE POTENTIAL ROLE OF SYNAPTIC VESICLE CYCLING-RELATED GENES IN ALZHEIMER\'S DISEASE
Junfeng Zeng, Ruihua Zhang, Huihua Xu, Chengwu Zhang, Li Lu
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BACKGROUND: Alzheimer's disease (AD) involves alterations in synaptic vesicle cycling (SVC), which significantly affect neuronal communication and function. Therefore, a thorough investigation into the potential roles of SVC-related genes (SVCRGs) in AD can enhance the identification of critical biomarkers that may influence disease progression and treatment responses.
METHODS: The datasets used in this study were sourced exclusively from public databases. By integrating differential expression analysis with Mendelian randomization (MR), we identified SVCRGs as biomarkers for AD. Functional characterization of these biomarkers was performed, followed by integration into a nomogram. Further investigation of immune infiltration in AD patients and healthy individuals was carried out. Ultimately, the potential cellular mechanisms of AD were explored through single-cell RNA sequencing (scRNA-seq) analysis.
RESULTS: ATP6V1D, ATP6V1G2, CLTB, and NSF were identified as biomarkers, exhibiting a positive correlation with each other and a downregulated expression in AD. These markers were pinpointed as protective factors for AD [odds ratio (OR) < 1, P < 0.05], with potential to reduce the risk of the disease. Integrated into a nomogram, they demonstrated satisfactory diagnostic performance and clinical utility, surpassing the use of single gene. They were collectively enriched in pathways related to "interferon gamma response", "inflammatory response", and "TNFα signaling via NFκB". Additionally, an increase in infiltration of 17 immune cell types in AD was noted, particularly cells associated with neuroinflammation such as activated CD8 T cells and various dendritic cells (DCs), suggesting an inflammatory milieu in AD while also displaying a negative correlation with the biomarkers. The cell types were further annotated, revealing specific expressions of biomarkers and uncovering the heterogeneity of excitatory neurons. A significant reduction in the overall number of excitatory neurons under AD conditions was observed, alongside consistent expression of biomarkers during the developmental stages of excitatory neurons.
CONCLUSION: By using MR, we firstly identified four SVCRGs as protective factors for AD, functioning through pathways associated with mitochondrial dysfunction, chronic inflammation, immune dysregulation, and neuronal damage. These genes had the potential to modulate immune cell infiltration activated in AD patients and exhibited cell-type-specific expression profiles within AD-related cellular contexts. Their findings provide novel insights and valuable references for future research on AD pathogenesis and therapeutic strategies.
CITATION:
Junfeng Zeng ; Ruihua Zhang ; Huihua Xu ; Chengwu Zhang ; Li Lu (2025): Integrative single-cell RNA sequencing and mendelian randomization analysis reveal the potential role of synaptic vesicle cycling-related genes in Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100097
LECANEMAB FOR EARLY ALZHEIMER\'S DISEASE: APPROPRIATE USE RECOMMENDATIONS FROM THE FRENCH FEDERATION OF MEMORY CLINICS
Nicolas Villain, Vincent Planche, Matthieu Lilamand, Charlotte Cordonnier, Maria Soto-Martin, Hélène Mollion, Stéphanie Bombois, Julien Delrieu, French Federation of Memory Clinics Work Group on Anti-Amyloid Immunotherapies
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Lecanemab, a monoclonal antibody targeting β-amyloid protofibrils, has shown promising results in a Phase III clinical trial for the treatment of early stages of Alzheimer's disease (AD) and has been approved by the European Medicines Agency. An Early Market Authorization could be submitted to the French regulatory agencies, potentially allowing for the drug's use in clinical practice in France in 2025.
To guide French clinicians in administering lecanemab in a standardized way, the French Federation of Memory Clinics has developed appropriate use recommendations for lecanemab that highlight relevant questions established to ensure an optimal risk-benefit ratio.
The recommendations emphasize that lecanemab treatment requires a comprehensive individualized evaluation of the risk-benefit ratio, which should occur in multidisciplinary meetings. When approved, the guidelines support the use of blood biomarkers, proposing specific cutoffs for patients eligible for lecanemab under restricted conditions. In addition to the European Medicines Agency restrictions in patients on anticoagulants, and APOE4 homozygotes, the guidelines recommend against lecanemab treatment for patients with high amyloid-related hemorrhagic risk such as probable cerebral amyloid angiopathy (Boston criteria v1.5) until further data become available. Additionally, we recommend that MRI monitoring be started before the third infusion to account for early Amyloid Related Imaging Abnormalities (ARIA) occurring on lecanemab. It is recommended to establish a specific clinical care pathway with protocols for patients with ARIA, with trained physicians and radiologists with expertise in neurological emergency and intensive care. Finally, a discontinuation protocol based on dementia severity assessment after 18 months of lecanemab treatment is suggested.
Access to lecanemab requires a personalized biological and genetic diagnosis of AD, which is currently not necessary in most cases. Therefore, the healthcare system must rapidly adjust to new diagnostic procedures and treatment delivery to ensure equal access for all individuals.
CITATION:
Nicolas Villain ; Vincent Planche ; Matthieu Lilamand ; Charlotte Cordonnier ; Maria Soto-Martin ; Hélène Mollion ; Stéphanie Bombois ; Julien Delrieu ; French Federation of Memory Clinics Work Group on Anti-Amyloid Immunotherapies (2025): Lecanemab for early Alzheimer's disease: Appropriate use recommendations from the French federation of memory clinics. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100094
FEASIBILITY OF COMPUTERIZED MOTOR, COGNITIVE AND SPEECH TESTS IN THE HOME: ANALYSIS OF TAS TEST IN 2,300 OLDER ADULTS
Guan Huang, Renjie Li, Eddy Roccati, Katherine Lawler, Aidan Bindoff, Anna King, James Vickers, Quan Bai, Jane Alty
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BACKGROUND: Early detection of Alzheimer's disease (AD) risk is crucial for dementia prevention. Tasmanian Test (TAS Test) is a novel, unsupervised, computerized assessment of motor, cognitive, and speech function designed to detect AD risk.
OBJECTIVES: To evaluate the feasibility, usability, and acceptability of TAS Test.
DESIGN AND SETTING: TAS Test was administered remotely at home and/or in a research facility, using personal computers.
PARTICIPANTS: 2,351 adults aged 50–89 years (mean 65.35), 71.76 % female, from Tasmania, Australia.
MEASUREMENTS: Completion rates, ease-of-use, distraction, test duration, and enjoyment scores. Demographics, computer literacy, cognition, and mood were analyzed.
RESULTS: Over 80 % completed motor and cognitive components with 92.8 % completing speech tests. 89.81 % found the duration acceptable. 80.90 % of remote and 83.46 % of onsite participants enjoyed the procedure. High usability and acceptability were reported, with age, gender, education, computer literacy, cognition and mood having minimal or no impact.
CONCLUSIONS: TAS Test demonstrated high completion rates and user satisfaction across a large community sample, supporting its feasibility as an unsupervised computerized assessment tool. Future research should address demographic representation and technical refinements.
CITATION:
Guan Huang ; Renjie Li ; Eddy Roccati ; Katherine Lawler ; Aidan Bindoff ; Anna King ; James Vickers ; Quan Bai ; Jane Alty (2025): Feasibility of computerized motor, cognitive and speech tests in the home: Analysis of TAS Test in 2,300 older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100081
REAL-WORLD DATASETS FOR THE INTERNATIONAL REGISTRY FOR ALZHEIMER\'S DISEASE AND OTHER DEMENTIAS (INRAD) AND OTHER REGISTRIES: AN INTERNATIONAL CONSENSUS
Robert Perneczky , David Darby , Giovanni B. Frisoni, Robert Hyde , Takeshi Iwatsubo, Catherine J. Mummery, Kee Hyung Park, Johan van Beek, Wiesje M. van der Flier, Frank Jessen
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BACKGROUND: Many dementia and Alzheimer's disease (AD) registries operate at local or national levels without standardization or comprehensive real-world data (RWD) collection. This initiative sought to achieve consensus among experts on priority outcomes and measures for clinical practice in caring for patients with symptomatic AD, particularly in the mild cognitive impairment and mild to moderate dementia stages.
OBJECTIVE: The primary aim was to define a minimum dataset (MDS) and extended dataset (EDS) to collect RWD in the new International Registry for AD and Other Dementias (InRAD) and other AD registries. The MDS and EDS focus on informing routine clinical practice, covering relevant comorbidities and safety, and are designed to be easily integrated into existing data capture systems.
METHODS AND RESULTS: An international steering committee (ISC) of AD clinician experts lead the initiative. The first drafts of the MDS and EDS were developed based on a previous global inter-societal Delphi consensus on outcome measures for AD. Based on the ISC discussions, a survey was devised and sent to a wider stakeholder group. The ISC discussed the survey results, resulting in a consensus MDS and EDS covering: patient profile and demographics; lifestyle and anthropometrics; co-morbidities and diagnostics; imaging; treatment; clinical characterization; safety; discontinuation; laboratory tests; patient and care partner outcomes; and interface functionality.
CONCLUSION: By learning from successful examples in other clinical areas, addressing current limitations, and proactively enhancing data quality and analytical rigor, the InRAD registry will be a foundation to contribute to improving patient care and outcomes in neurodegenerative diseases.
CITATION:
Robert Perneczky ; David Darby ; Giovanni B. Frisoni ; Robert Hyde ; Takeshi Iwatsubo ; Catherine J. Mummery ; Kee Hyung Park ; Johan van Beek ; Wiesje M. van der Flier ; Frank Jessen (2025): Real-world datasets for the International Registry for Alzheimer's Disease and Other Dementias (InRAD) and other registries: An international consensus. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100096
MULTISENSORY STIMULATION REDUCES NEUROPSYCHIATRIC SYMPTOMS AND ENHANCES COGNITIVE FUNCTION IN OLDER ADULTS WITH DEMENTIA: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Tiara Octary, Melati Fajarini, Hidayat Arifin, Ruey Chen, Chien-Mei Sung, Li-Fang Chang, Chia-Hui Wang, Kondwani Joseph Banda, Kuei-Ru Chou
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OBJECTIVE: Multisensory stimulation defined as engaging multiple senses (visual, olfactory, auditory, gustatory, and tactile), has been demonstrated to improve older adults’ general health. However, its effectiveness in mitigating neuropsychiatric symptoms (NPSs) and cognitive deficits in older adults with dementia remains unclear. This meta-analysis evaluated the efficacy of multisensory stimulation in ameliorating NPSs and improving overall cognitive function in older adults with dementia.
METHODS: We searched eight databases to September 2024 without restriction. Older adults with all stages of dementia aged 65 years and above were included. To estimate the pooled effect size, Hedge's g (g) values were calculated using a random-effects model. Heterogeneity was assessed using the Q, I², and τ² statistics. Subgroup and meta-regression analyses were performed to identify moderators. Publication bias was assessed using Begg and Mazumdar's rank correlation and Egger's linear regression tests.
RESULTS: This review included 16 studies (974 patients). Multisensory stimulation significantly reduced agitation (g= −0.96; 95 %CI= −1.44, −0.48), apathy (g= −1.27; 95 %CI= −2.08, −0.46), and depression (g= −0.28; 95 %CI= −0.48, −0.07). Moreover, the intervention significantly improved overall cognitive function (g= 0.30; 95 %CI= 0.09, 0.52). However, multisensory stimulation had no significant effect on anxiety (g= −0.81; 95 %CI= −1.79, 0.17). Significant heterogeneity was observed in agitation, apathy, and anxiety. Moreover, meta-regression analyses by educational level (junior high school and above) revealed significant moderators in agitation.
CONCLUSIONS: Multisensory stimulation shows promise as a non-pharmacological intervention for older adults with dementia. It may effectively mitigate NPSs and improve cognitive function into clinical practice as an alternative therapeutic.
CITATION:
Tiara Octary ; Melati Fajarini ; Hidayat Arifin ; Ruey Chen ; Chien-Mei Sung ; Li-Fang Chang ; Chia-Hui Wang ; Kondwani Joseph Banda ; Kuei-Ru Chou (2025): Multisensory stimulation reduces neuropsychiatric symptoms and enhances cognitive function in older adults with dementia: A meta-analysis of randomized controlled trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100091
BEHAVIOUR CHANGE TECHNIQUES USED IN INTERVENTIONS TARGETING DEMENTIA RISK FACTORS AMONGST OLDER ADULTS IN RURAL AND REMOTE AREAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Laura Dodds, Kay Deckers, Celia B. Harris, Joyce Siette
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Behavioural interventions targeting health risk factors within rural areas are often not tailored to effectively address the needs and socio-environmental barriers to access and behaviour change faced by these communities. Little is known about the underlying behaviour change mechanisms that contribute to reducing dementia risk for communities living in regional and rural areas. This systematic review and meta-analysis aimed to summarise the effectiveness of behavioural interventions targeting late-life single modifiable dementia risk factors (physical inactivity, poor diet, social isolation and depression) and the mechanisms used to contribute to behaviour change. Six databases were searched to identify regional and rural behavioural interventions targeting modification of late-life dementia risk behaviours between 2000 and 2024. Behaviour change techniques (BCTs) and outcomes for each intervention were extracted. Where possible, meta-analyses were performed to assess the effectiveness of the behavioural intervention on outcomes related to dementia risk. Out of 42,529 articles, 49 studies were included: 22 on physical inactivity, 6 on poor diet, 9 on social isolation, and 12 on depression. Many BCT categories were applied (M = 14.8, SD = 10), with high use of goals and planning (49/49 interventions; 100 %), shaping knowledge (47/49 interventions; 95.9 %), social support (43/49 interventions; 87.8 %) and comparison of outcomes (38/49 interventions; 77.6 %). Social isolation interventions used the most BCTs (M = 18.3; SD = 8.5), followed by depression (M = 17.6; SD = 10.7), physical inactivity (M = 16.0; SD = 11.5), and poor diet (M = 5.2; SD = 3.1). Although effectiveness was limited across interventions, apart from cognitive behavioural therapy for depression (SMD −0.39, 95 % CI −0.55 to −0.24), future programs targeting dementia risk factors would benefit from incorporation of BCTs. Simultaneously, consideration of the socio-environmental context, accessibility, and community involvement in rural and regional areas may improve the sustainability of interventions.
CITATION:
Laura Dodds ; Kay Deckers ; Celia B. Harris ; Joyce Siette (2025): Behaviour change techniques used in interventions targeting dementia risk factors amongst older adults in rural and remote areas: A systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100093
INTERACTIONS OF PHYSICAL ACTIVITY AND LUNG FUNCTION ON COGNITIVE HEALTH IN OLDER ADULTS: JOINT ASSOCIATION AND MEDIATION ANALYSIS
Peng Hu, Dan Song, Tian Heng, Ling-Ling Yang, Chuan-Chuan Bai, Rui He, Tao Liu, Ya-Xi Luo, Xiu-Qing Yao
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BACKGROUND: Maintaining cognitive health in old adults has become a significant public health challenge, with lung function and physical activity (PA) as essential modifiable factors. However, the joint and mediation effects of these two factors with cognition remain unclear.
OBJECTIVES: This study assesses the joint association and mediation effects of lung function and PA with cognition.
DESIGN, SETTING, AND PARTICIPANTS: We utilized cross-sectional data from the 2011–2012 U.S. National Health and Nutrition Examination Survey, including adults aged 60–79 assessed for lung function, PA, and cognition.
MAIN OUTCOMES AND MEASURES: Lung function included forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF) and FEV1/FVC. PA was assessed using the Global Physical Activity Questionnaire, covering occupational PA (OPA), transportation-related PA (TPA), and leisure-time PA (LTPA). Cognition was evaluated using the Digit Symbol Substitution Test, Animal Fluency Test, Delayed Recall Test and Immediate Recall Test. Weighted multiple linear regression models were used to analyze the separate and joint associations of lung function and PA with cognition, while also exploring potential mediation effects between these factors.
RESULTS: A total of 927 participants, representing 35,525,782 U.S. residents, were included, with a weighted median age of 65 (IQR, 63 -71) years, and 53.6 % were female. The results showed a significant positive association between lung function and cognitive function, with FEV1, FVC, and PEF all positively correlated, while the FEV1/FVC showed no notable link. Further analysis revealed the best cognitive performance observed in participants with active LTPA and the highest quartile of lung function, indicating a joint association of LTPA and lung function with cognition. Mediation analysis indicated that lung function mediated 24.1 % (95 %CI: 6.3 % - 47.0 %, P = 0.03) of the relationship between LTPA and cognition, while cognition mediated 10.2 % (95 %CI: 0.5 % - 27.0 %, P = 0.04) of the relationship between LTPA and lung function.
CONCLUSION: Lung function and cognition may have a bidirectional relationship. The combination of active LTPA and better lung function was strongly associated with higher cognition, highlighting the need to strengthen exercise focused on lung function to maintain cognitive health in older adults.
CITATION:
Peng Hu ; Dan Song ; Tian Heng ; Ling-Ling Yang ; Chuan-Chuan Bai ; Rui He ; Tao Liu ; Ya-Xi Luo ; Xiu-Qing Yao (2025): Interactions of physical activity and lung function on cognitive health in older adults: Joint association and mediation analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100090
BIOFLUID BIOMARKER CHANGES FOLLOWING TREATMENT WITH SABIRNETUG (ACU193) IN INTERCEPT-AD, A PHASE 1 TRIAL IN EARLY ALZHEIMER\'S DISEASE
Erika N. Cline, Daniel Antwi-Berko, Karen Sundell, Elizabeth Johnson, Maddelyn Hyland, Hao Zhang, Hugo Vanderstichele, June Kaplow, Robert A. Dean, Erik Stoops, Eugeen Vanmechelen, Marleen J.A. Koel-Simmelink, Charlotte E. Teunissen, Gopalan Sethuraman, Todd Feaster, Eric Siemers, Jasna Jerecic
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OBJECTIVE: Sabirnetug (ACU193) is a humanized monoclonal antibody selective for soluble amyloid beta oligomers (AβOs), synaptotoxins that are early and persistent triggers of Alzheimer's disease (AD). Sabirnetug pharmacodynamics were examined in the INTERCEPT-AD phase 1 study in mild cognitive impairment and mild dementia due to AD (NCT04931459) using biofluid biomarkers associated with Aβ and tau pathology, synaptic dysfunction, neuroinflammation, and neurodegeneration.
METHODS: INTERCEPT-AD was a randomized, first-in-human study of sabirnetug versus placebo administered as a single (SAD; 2, 10, 25, 60 mg/kg) or multiple (MAD; three doses of 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) ascending doses. Biomarkers were measured pre-/post-dose in CSF and EDTA-plasma. Correlations of biomarker changes versus dose, exposure duration, and target engagement were determined.
RESULTS: In MAD cohorts, CSF pTau181 decreased significantly (60 mg/kg Q4W, p = 0.049). VAMP2 decreased significantly at all doses (p ≤ 0.041); neurogranin decreased significantly at 60 mg/kg Q4W (p = 0.037). Aβ1-42/Aβ1–40 trended upward with sabirnetug dose. Aβ1–42/Aβ1–40 and neurogranin changes correlated with sabirnetug-AβO target engagement (p ≤ 0.01). Decreases in tTau, VAMP2, and neurogranin correlated with exposure duration (p ≤ 0.007). Plasma pTau181, pTau217, GFAP, and NfL trended lower.
DISCUSSION: Following three sabirnetug doses, changes in CSF and plasma biomarkers were observed. The CSF biomarker response increased with increasing dose and exposure duration, consistent with previous reports that sabirnetug reaches the central compartment and engages its AβO target. The ongoing phase 2 ALTITUDE-AD study (NCT06335173) will test whether sabirnetug's pharmacodynamic effects can be substantiated with a larger sample size and longer treatment duration.
CITATION:
Erika N. Cline ; Daniel Antwi-Berko ; Karen Sundell ; Elizabeth Johnson ; Maddelyn Hyland ; Hao Zhang ; Hugo Vanderstichele ; June Kaplow ; Robert A. Dean ; Erik Stoops ; Eugeen Vanmechelen ; Marleen J.A. Koel-Simmelink ; Charlotte E. Teunissen ; Gopalan Sethuraman ; Todd Feaster ; Eric Siemers ; Jasna Jerecic (2025): Biofluid biomarker changes following treatment with sabirnetug (ACU193) in INTERCEPT-AD, a phase 1 trial in early Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100082
ELIGIBILITY FOR DONANEMAB TRIAL IN A POPULATION-BASED STUDY OF COGNITIVE AGING
Katherine E. Jones, Jeremiah A. Aakre, Anna M. Castillo, Vijay K. Ramanan, Walter K. Kremers, Clifford R. Jack Jr, Prashanthi Vemuri, Christopher G Schwarz, Val J. Lowe, David S. Knopman, Ronald C. Petersen, Jonathan Graff-Radford, Maria Vassilaki
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The study aimed to assess eligibility for donanemab phase 3 trial in participants of the Mayo Clinic Study of Aging with mild cognitive impairment (MCI) or mild dementia consistent with Alzheimer's disease (AD) clinical syndrome, positive brain amyloid burden, and available tau PET. There were 817 study participants, 60–85 years old, with MCI or dementia consistent with AD clinical syndrome. Applying the Mini-Mental State Examination criteria (20 to 28) and excluding participants with imaging contraindications reduced the sample to 769; 275 participants had amyloid PET available, of whom 130 had also tau PET at the same visit; 56 participants were amyloid positive, had tau PET available at the same visit, and of those, 27 had evidence of tau pathology measured by 18F-flortaucipir PET imaging. Additional eligibility criteria reduced the eligible participants to 23 % (13 out of 56 participants). Neuroimaging findings, central nervous system exclusions, and history of malignancy were the major exclusions.
CITATION:
Katherine E. Jones ; Jeremiah A. Aakre ; Anna M. Castillo ; Vijay K. Ramanan ; Walter K. Kremers ; Clifford R. Jack Jr ; Prashanthi Vemuri ; Christopher G Schwarz ; Val J. Lowe ; David S. Knopman ; Ronald C. Petersen ; Jonathan Graff-Radford ; Maria Vassilak (2025): Eligibility for donanemab trial in a population-based study of cognitive aging. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100088
CHARACTERIZING AND VALIDATING 12-MONTH RELIABLE COGNITIVE CHANGE IN EARLY-ONSET ALZHEIMER\'S DISEASE FOR USE IN CLINICAL TRIALS
Dustin B. Hammers, Jane Musema, Ani Eloyan, Maryanne Thangarajah, Alexander Taurone, Renaud La Joie, Alexandra Touroutoglou, Prashanthi Vemuri, Joel Kramer, Paul Aisen, Jeffrey L. Dage, Kelly N. Nudelman, Kala Kirby, Alireza Atri, David Clark, Gregory S. Day, Ranjan Duara, Neill R. Graff-Radford, Ian Grant, Lawrence S. Honig, Erik C.B. Johnson, David T. Jones, Joseph C. Masdeu, Mario F. Mendez, Kyle Womack, Erik Musiek, Chiadi U. Onyike, Meghan Riddle, Emily Rogalski, Steven Salloway, Sharon J. Sha, Raymond Scott Turner, Thomas S. Wingo, David A. Wolk, Maria C. Carrillo, Gil D. Rabinovici, Bradford C. Dickerson, Liana G. Apostolova, the LEADS Consortium
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BACKGROUND: As literature suggests that Early-Onset Alzheimer's Disease (EOAD) and late-onset AD may differ in important ways, need exists for randomized clinical trials for treatments tailored to EOAD. Accurately measuring reliable cognitive change in individual patients with EOAD will have great value for these trials.
OBJECTIVES: The current study sought to characterize and validate 12-month reliable change from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) neuropsychological battery.
DESIGN: Standardized regression-based (SRB) prediction equations were developed from age-matched cognitively intact participants within LEADS, and applied to clinically impaired participants from LEADS.
SETTING: Participants were recruited from outpatient academic medical centers.
PARTICIPANTS: Participants were enrolled in LEADS and diagnosed with amyloid-positive EOAD (n = 189) and amyloid-negative early-onset cognitive impairment not related to AD (EOnonAD; n = 43).
MEASUREMENT: 12-month reliable change (Z-scores) was compared between groups across cognitive domain composites, and distributions of individual participant trajectories were examined. Prediction of Z-scores by common AD biomarkers was also considered.
RESULTS: Both EOAD and EOnonAD displayed significantly lower 12-month follow-up scores than were predicted based on SRB equations, with declines more pronounced for EOAD across several domains. AD biomarkers of cerebral β-amyloid, tau, and EOAD-specific atrophy were predictive of 12-month change scores.
CONCLUSIONS: The current results support including EOAD patients in longitudinal clinical trials, and generate evidence of validation for using 12-month reliable cognitive change as a clinical outcome metric in clinical trials in EOAD cohorts like LEADS. Doing so will enhance the success of EOAD trials and permit a better understanding of individual responses to treatment.
CITATION:
Dustin B. Hammers ; Jane Musema ; Ani Eloyan ; Maryanne Thangarajah ; Alexander Taurone ; Renaud La Joie ; Alexandra Touroutoglou ; Prashanthi Vemuri ; Joel Kramer ; Paul Aisen ; Jeffrey L. Dage ; Kelly N. Nudelman ; Kala Kirby ; Alireza Atri ; David Clark ; Gregory S. Day ; Ranjan Duara ; Neill R. Graff-Radford ; Ian Grant ; Lawrence S. Honig ; Erik C.B. Johnson ; David T. Jones ; Joseph C. Masdeu ; Mario F. Mendez ; Kyle Womack ; Erik Musiek ; Chiadi U. Onyike ; Meghan Riddle ; Emily Rogalski ; Steven Salloway ; Sharon J. Sha ; Raymond Scott Turner ; Thomas S. Wingo ; David A. Wolk ; Maria C. Carrillo ; Gil D. Rabinovici ; Bradford C. Dickerson ; Liana G. Apostolova ; the LEADS Consortium (2025): Characterizing and validating 12-month reliable cognitive change in Early-Onset Alzheimer's Disease for use in clinical trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100075
ASSOCIATION OF DIETARY DIVERSITY, GENETIC SUSCEPTIBILITY, AND THE RISK OF INCIDENT DEMENTIA: A PROSPECTIVE COHORT STUDY
Boyue Zhao, Bolun Cheng, Xinyang Li, Jinyu Xia, Yifan Gou, Meijuan Kang, Jingni Hui, Ye Liu, Ruixue Zhou, Chen Liu, Bingyi Wang, Panxing Shi, Feng Zhang
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BACKGROUND: Previous studies have revealed how single foods or nutrients affect dementia, but the evidence for a potential link between dietary diversity and dementia is inconsistent.
OBJECTIVES: This study aimed to evaluate the association between dietary diversity and the risk of incident dementia.
DESIGN, SETTING AND PARTICIPANTS : This prospective study included 104,572 white participants without dementia at baseline recruited between 2006 and 2010 from the UK Biobank.
MEASUREMENTS: Dietary Diversity Score (DDS) was acquired through the Oxford WebQ's 24-hour dietary recall survey spanning from 2009 to 2012. Cox proportional hazards models were used to estimate the associations between DDS, diversity scores of food groups and the risk of incident dementia. Stratified analyses were subsequently conducted to assess the potential variations across different demographic, socioeconomic, and genetic risk groups.
RESULTS: Over a median follow-up period of 10.44 years, 725 participants developed incident dementia. A higher DDS was associated with a lower risk of incident dementia (HR: 0.95; 95 % CI: 0.93–0.97). Stratified analyses revealed statistical significance in this association for individuals under 65 years old (HR: 0.95; 95 % CI: 0.92–0.98), and those with higher polygenic risk scores (PRS; HR: 0.92; 95 % CI: 0.89–0.95). Among five food groups, a higher diversity score for meat and protein alternatives was associated with a lower risk of dementia (HR: 0.92; 95 % CI: 0.86–0.99).
CONCLUSION: Enhancing dietary diversity reduces dementia risk, and is potentially influenced by genetic predisposition. Consuming a diverse range of foods may be an effective strategy against dementia.
CITATION:
Boyue Zhao ; Bolun Cheng ; Xinyang Li ; Jinyu Xia ; Yifan Gou ; Meijuan Kang ; Jingni Hui ; Ye Liu ; Ruixue Zhou ; Chen Liu ; Bingyi Wang ; Panxing Shi ; Feng Zhang (2025): Association of dietary diversity, genetic susceptibility, and the risk of incident dementia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100078
DIAGNOSTIC AND DISCRIMINATIVE ACCURACY OF PLASMA PHOSPHORYLATED TAU 217 FOR SYMPTOMATIC ALZHEIMERʼS DISEASE IN A CHINESE COHORT
Li-Min Li, Ping Che, Dequan Liu, Yu Wang, Jia Li, Dian He, Tao Liu, Nan Zhang
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BACKGROUND: Plasma phosphorylated tau at threonine 217 (p-tau217) measured with an ultrasensitive immunoassay method has been demonstrated to be an optimal biomarker for Alzheimer's disease (AD).
OBJECTIVES: The aim of this study was to establish the reference interval for plasma p-tau217 in Chinese individuals and evaluate its diagnostic value in symptomatic AD.
DESIGN, SETTING, PARTICIPANTS: We recruited 150 cognitively unimpaired (CU) individuals, 60 patients with AD dementia, 30 patients with mild cognitive impairment (MCI) due to AD, 40 patients with frontotemporal lobar degeneration (FTLD), and 70 patients with subcortical ischaemic vascular dementia (SIVD).
MEASUREMENTS: The concentrations of plasma p-tau217, total tau, amyloid-beta (Aβ)42 and Aβ40 were measured with a single-molecule array.
RESULTS: Plasma p-tau217 outperformed other biomarkers in discriminating AD patients from CU controls, FTLD patients, and SIVD patients (AUC = 0.983, 0.936, 0.892) and discriminating MCI patients from CU controls (AUC = 0.943). The plasma p-tau217 level was negatively correlated with memory in patients with symptomatic AD.
CONCLUSION: The diagnostic accuracy of plasma p-tau217 was exceptional for AD, even at early stages, in the Chinese population.
CITATION:
Li-Min Li ; Ping Che ; Dequan Liu ; Yu Wang ; Jia Li ; Dian He ; Tao Liu ; Nan Zhang (2025): Diagnostic and discriminative accuracy of plasma phosphorylated tau 217 for symptomatic Alzheimerʼs disease in a Chinese cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100092
THE IMPACT OF PRE-ANALYTICAL FACTORS ON PLASMA BIOMARKERS FOR ALZHEIMER\'S DISEASE: THE ASPREE HEALTHY AGEING BIOBANK
Zimu Wu, Michelle M. Mielke, Anne M. Murray, James Phung, Alice Owen, Robyn L. Woods, Danni Li, Jo Wrigglesworth, Joanne Ryan
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BACKGROUND: The conditions under which samples were collected, processed, and stored in biobanks may influence Alzheimer's disease (AD) biomarker levels.
OBJECTIVES: This study aims to investigate whether a range of pre-analytical factors influence plasma levels of AD biomarkers.
METHODS: Data were obtained from the ASPREE Healthy Ageing Biobank, a cohort of healthy community-dwelling older individuals aged 70+ years in Australia. Five biomarkers were measured using plasma from 11,868 individuals: phosphorylated-tau181 (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-beta 42 and 40 (Aβ42/Aβ40). Linear regression examined the association between pre-analytical factors and biomarker levels.
RESULTS: Participants were aged 70–96 years, and 54 % were female. The mean storage time for samples was 10.6 years (range: 7.7–13.5). Some significant associations were identified between pre-analytical factors and biomarkers, in particular for p-tau181, but the effect sizes were small. Weak negative associations were found between p-tau181 and the time from venepuncture to laboratory (transport) (β: −0.82, p = 0.03), laboratory processing to frozen storage (β:−1.56, p < 0.001), and total years of storage (β: −0.45, p = 0.007), while a positive association was found with intermediate storage at −20 °C/−30 °C compared to −80 °C (β: 2.24, p = 0.004). Longer fasting time was associated with higher levels of both NfL (β: 0.15, p < 0.001) and GFAP (β: 1.75, p < 0.001).
CONCLUSION: Following standard operating procedures, AD biomarkers can be measured in plasma from biobanks stored for up to 13 years, with minimal impact from long-term storage or other pre-analytical factors.
CITATION:
Zimu Wu ; Michelle M. Mielke ; Anne M. Murray ; James Phung ; Alice Owen ; Robyn L. Woods ; Danni Li ; Jo Wrigglesworth ; Joanne Ryan (2025): The impact of pre-analytical factors on plasma biomarkers for Alzheimer's disease: The ASPREE Healthy Ageing Biobank. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100058
JOINT ENSEMBLE LEARNING-BASED RISK PREDICTION OF ALZHEIMER\'S DISEASE AMONG MILD COGNITIVE IMPAIRMENT PATIENTS
Tianyuan Guan, Lei Shang, Peng Yang, Zhijun Tan, Yue Liu, Chunling Dong, Xueying Li, Zuxuan Hu, Haixia Su, Yuhai Zhang
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OBJECTIVE: Due to the recognition for the importance of early intervention in Alzheimer's disease (AD), it is important to focus on prevention and treatment strategies for mild cognitive impairment (MCI). This study aimed to establish a risk prediction model for AD among MCI patients to provide clinical guidance for primary medical institutions.
METHODS: Data from MCI subjects were obtained from the NACC. Importance ranking and the SHapley Additive exPlanations (SHAP) method for the Random Survival Forest (RSF) and Extreme Gradient Boosting (XGBoost) algorithms in ensemble learning were adopted to select the predictors, and hierarchical clustering analysis was used to mitigate multicollinearity. The RSF, XGBoost and Cox proportional hazard regression (Cox) models were established to predict the risk of AD among MCI patients. Additionally, the effects of the three models were evaluated.
RESULTS: A total of 3674 subjects with MCI were included. Thirteen predictors were ultimately identified. In the validation set, the concordance indices were 0.781 (RSF), 0.781 (XGBoost), and 0.798 (Cox), and the Integrated Brier Score was 0.087 (Cox). The prediction effects of the XGBoost and RSF models were not better than those of the Cox model.
CONCLUSION: The ensemble learning method can effectively select predictors of AD risk among MCI subjects. The Cox proportional hazards regression model could be used in primary medical institutions to rapidly screen for the risk of AD among MCI patients once the model is fully clinically validated. The predictors were easy to explain and obtain, and the prediction of AD was accurate.
CITATION:
Tianyuan Guan ; Lei Shang ; Peng Yang ; Zhijun Tan ; Yue Liu ; Chunling Dong ; Xueying Li ; Zuxuan Hu ; Haixia Su ; Yuhai Zhang (2025): Joint ensemble learning-based risk prediction of Alzheimer's disease among mild cognitive impairment patients. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100083
PREDICTING COGNITIVE DECLINE: DEEP-LEARNING REVEALS SUBTLE BRAIN CHANGES IN PRE-MCI STAGE
Ling Yue, Yongsheng Pan, Wei Li, Junyan Mao, Bo Hong, Zhen Gu, Mingxia Liu, Dinggang Shen, Shifu Xiao
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BACKGROUND: Mild cognitive impairment (MCI) and preclinical MCI (e.g., subjective cognitive decline, SCD) are considered risk states of dementia, such as Alzheimer's Disease (AD). However, it is challenging to accurately predict conversion from normal cognition (NC) to MCI, which is important for early detection and intervention. Since neuropathological changes may have occurred in the brain many years before clinical AD, we sought to detect the subtle brain changes in the pre-MCI stage using a deep-learning method based on structural Magnetic Resonance Imaging (MRI).
OBJECTIVES: To discover early structural neuroimaging changes that differentiate between stable and progressive cognitive status, and to establish a predictive model for MCI conversion.
DESIGN, SETTING AND PARTICIPANTS: We first created a unique deep-learning framework for pre-AD conversion prediction through the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1) database (n = 845). Then, we tested the model on ADNI-2 (n = 321, followed 3 years) and our private study (n = 109), the China Longitudinal Aging Study (CLAS), to validate the rationality for pre-MCI conversion prediction. The CLAS is a 7-year community-based cohort study in Shanghai. Our framework consisted of two steps: 1) a single-ROI-based network (SRNet) for identifying informative regions in the brain, and 2) a multi-ROI-based network (MRNet) for pre-AD conversion prediction. We then utilized these "ROI-based deep learning" neural networks to create a composite score using advanced algorithm-building. We coined this score as the Progressive Index (PI), which serves as a metric for assessing the propensity of AD conversion. Ultimately, we employed the PI to gauge its predictive capability for MCI conversion in both ADNI-2 and CLAS datasets.
MEASUREMENTS: We primarily utilized baseline T1-weighted MRI scans to identify the most discriminative brain regions and subsequently developed the PI in both training and validation datasets. We compared the PI across different cognitive groups and conducted logistic regression models along with their AUCs, adjusting for education level, gender, neuropsychological test scores, and the presence of comorbid conditions.
RESULTS: We trained the SRNet and MRNet using 845 subjects from ADNI-1 with baseline MRI data, in which AD and progressive MCI (converting to AD within 3 years) patients were considered as positive samples, while NC and stable MCI (remaining stable for 3 years) subjects were considered as negative samples. The convolutional neural networks identified the top 10 regions of interest (ROIs) for distinguishing progressive from stable cases. These key brain regions included the hippocampus, amygdala, temporal lobe, insula, and anterior cerebellum. A total of 321 subjects from ADNI-2, including 209 NC (18 progressive NC (pNC), 113 stable NC (sNC), and 78 remaining NC (rNC)) and 112 SCD (11 pSCD, 5 sSCD, and 96 rSCD), as well as 109 subjects from CLAS, including 17 sNC, 16 pNC, 52 sSCD and 24 pSCD participated in the test set, separately. We found that the PI score effectively sorted all subjects by their stages (stable vs progressive). Furthermore, the PI score demonstrated excellent discrimination between the two outcomes in the CLAS data(p<0.001), even after controlling for age, gender, education level, depression symptoms, anxiety symptoms, somatic diseases, and baseline MoCA score. Better performance for prediction progression to MCI in CLAS was obtained when the PI score was combined with clinical measures (AUC=0.812; 95 %CI: 0.725–0.900).
CONCLUSIONS: This study effectively predicted the progression to MCI among order individuals at normal cognition state by deep learning algorithm with MRI scans. Exploring the key brain alterations during the very early stages, specifically the transition from NC to MCI, based on deep learning methods holds significant potential for further research and contributes to a deeper understanding of disease mechanisms.
CITATION:
Ling Yue ; Yongsheng Pan ; Wei Li ; Junyan Mao ; Bo Hong ; Zhen Gu ; Mingxia Liu ; Dinggang Shen ; Shifu Xiao (2025): Predicting cognitive decline: Deep-learning reveals subtle brain changes in pre-MCI stage. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100079
THE INTERACTION BETWEEN CIRCADIAN SYNDROME AND GENETIC SUSCEPTIBILITY IN THE RISK OF INCIDENT DEMENTIA: A LONGITUDINAL COHORT STUDY
Linling Yu, Wei Liu, Chenqi Liao, Na Shen, Anding Liu, Liming Cheng, Xiong Wang
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BACKGROUND: Despite growing interest in circadian disturbances as potential triggers for dementia, the specific impact of circadian syndrome (CircS) on dementia incidence remains poorly understood. Moreover, the role of genetic susceptibility modulating these effects remains to be explored.
METHODS: Dementia-free participants from the UK Biobank cohort were included in the analysis. To evaluate the association between CircS and the incidence of dementia, as well as the modifying influence of genetic susceptibility on this relationship, Cox proportional hazards models were utilized.
RESULTS: During a median follow-up period of 14.55 years, 3,965 incident dementia cases were documented. CircS was found to significantly increased the risk of incident dementia, with a hazard ratio (HR) of 1.401 (95 % confidence interval [CI]: 1.296, 1.516). Compared to a CircS score of ≤3, mild CircS (HR: 1.259, 95 % CI: 1.146–1.383), moderate CircS (HR: 1.667, 95 % CI: 1.461–1.903), and severe CircS (HR: 2.028, 95 % CI: 1.397–2.944) were all significantly associated with an elevated risk of dementia. There were significant multiplicative interactions between CircS and genetic susceptibility (Pinteraction<0.001). Participants with both a high polygenic risk score (PRS) and CircS had the highest risk of incident dementia (HR: 2.551, 95 % CI: 2.169, 3.001), compared to those with a low PRS and no CircS.
CONCLUSIONS: CircS was associated with an increased risk of dementia, which might be aggravated by genetic susceptibility.
CITATION:
Linling Yu ; Wei Liu ; Chenqi Liao ; Na Shen ; Anding Liu ; Liming Cheng ; Xiong Wang (2025): The interaction between circadian syndrome and genetic susceptibility in the risk of incident dementia: A longitudinal cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100089
LMTK2 AND CRB1 ARE TWO NOVEL RISK GENES FOR ALZHEIMER\'S DISEASE IN HAN CHINESE
Xuewen Xiao, Hui Liu, Rui Yao, Yunni Li, Xinxin Liao, Yingzi Liu, Yafang Zhou, Junling Wang, Beisha Tang, Bin Jiao, Jinchen Li, Lu Shen, Shilin Luo
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BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with a substantial genetic background. However, its underlying genetic architecture remains to be elucidated.
METHODS: In this study, we performed whole-exome sequencing in 282 familial and/or early-onset AD patients and 1086 cognitively normal controls in the Han Chinse populations. According to minor allele frequency, variants were divided into common variants (MAF ≥ 0.01) and rare variants (MAF < 0.01). Common variant-based association analysis and gene-based association test aggregating rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal, respectively. We replicated the significant results by using the same AD samples and controls from whole genome sequencing (n = 1879). Furthermore, we determined the functions of the novel AD risk genes in vitro.
RESULTS: Common variants association analysis revealed that APOE rs429358 reached statistical whole-exome significance. Gene-level aggregation testing identified that rare damaging variants in LMTK2 and CRB1 conferred risk to AD. All variants are located in highly conserved amino acid regions and are predicted to be damaging. Furthermore, functional studies showed that LMTK2 rare damaging variants (R234P and S974G) enhanced tau phosphorylation levels, tau aggregates formation, and Aβ generation. Meanwhile, the CRB1 Y556X variant caused incomplete translation of CRB1 protein and increased the Aβ42 level and Aβ42/Aβ40 ratio.
CONCLUSION: Our findings indicated that LMTK2 and CRB1 are two novel AD risk genes in Han Chinese, which may provide promising targets for diagnosis and intervention.
CITATION:
Xuewen Xiao ; Hui Liu ; Rui Yao ; Yunni Li ; Xinxin Liao ; Yingzi Liu ; Yafang Zhou ; Junling Wang ; Beisha Tang ; Bin Jiao ; Jinchen Li ; Lu Shen ; Shilin Luo (2025): LMTK2 and CRB1 are two novel risk genes for Alzheimer's disease in Han Chinese. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100087
LETTER TO THE EDITOR: REEVALUATING THE SLEEP-DEMENTIA LINK: METHODOLOGICAL GAPS AND FUTURE DIRECTIONS
Julián Benito-León, Carla María Benito-Rodríguez
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CITATION:
Julián Benito-León ; Carla María Benito-Rodríguez (2025): Letter to the Editor: Reevaluating the sleep-dementia link: Methodological gaps and future directions. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100085
WHITE MATTER HYPERINTENSITY SEVERITY MODIFIES GUT METABOLITE ASSOCIATION WITH COGNITIVE OUTCOMES
Naruchorn Kijpaisalratana, Chia-Ling Phuah, Zsuzsanna Ament, Varun M. Bhave, Ana-Lucia Garcia-Guarniz, Jonathan Duskin, Catharine A. Couch, M. Ryan Irvin, W. Taylor Kimberly, Alzheimer\'s Disease Neuroimaging Initiative, Alzheimer Disease Metabolomics Consortium
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BACKGROUND: Gut microbiome-associated metabolites and white matter hyperintensities (WMH) are independently associated with cognitive impairment. However, it is unclear if gut metabolites and WMH interact to influence dementia.
OBJECTIVES: To examine the association between gut microbial metabolites and cognitive outcomes and assess whether the severity of baseline WMH would impact associations between gut microbial metabolites and cognitive outcomes.
DESIGN: Cross-sectional design. Setting: Cohort of individuals who are clinically normal, mild cognitive impairment, or Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants: A total of 578 participants with available baseline 3.0T 2D-Fluid Attenuation Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) scans and baseline gut microbial metabolite measurement were included in the analysis.
MEASUREMENTS: Gut metabolite measurements and automated WMH volume estimations were obtained from FLAIR MRI and were used to assess the association and interaction with cognitive impairment.
RESULTS: Of 104 metabolites studied, glycodeoxycholic acid (GDCA) surpassed the false discovery rate and was associated the Alzheimer's Disease Assessment Scale-Cognitive Subscale version 13 (ADAS-Cog13) score (β = 0.12, 95 % CI = 0.05–0.20, p = 0.001) and cognitive impairment determined by mini-mental status exam (MMSE) (OR = 2.11, 95 % CI = 1.41–3.15, p < 0.001). GDCA was associated with higher ADAS-Cog13 in participants with low WMH burden (β = 0.21, 95% CI = 0.10–0.32, p < 0.001) but not in participants with high WMH burden (β = 0.04, 95 % CI = -0.07 to 0.14, p = 0.48; interaction p = 0.02).
CONCLUSION: An elevated level of GDCA was associated with worse cognition. WMH severity modified the association between GDCA and cognitive outcomes.
CITATION:
Naruchorn Kijpaisalratana ; Chia-Ling Phuah ; Zsuzsanna Ament ; Varun M. Bhave ; Ana-Lucia Garcia-Guarniz ; Jonathan Duskin ; Catharine A. Couch ; M. Ryan Irvin ; W. Taylor Kimberly ; Alzheimer's Disease Neuroimaging Initiative ; Alzheimer Disease Metabolomics Consortium (2025): White matter hyperintensity severity modifies gut metabolite association with cognitive outcomes. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100086
PHYSICAL AND MENTAL DEMANDS OF WORK ASSOCIATED WITH DEMENTIA RISK IN LATER LIFE
Hang-Ju Yang, Yun-Chieh Yang, Chih-Cheng Hsu, Wan-Ju Cheng
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BACKGROUND: Work occupies a significant portion of adult life, and both cognitive stimulation and physical activity have been suggested as factors that may lower dementia risk in later life.
OBJECTIVES: To examine the association between mental and physical demands at work and the risk of dementia.
DESIGN: A cohort study.
SETTING: Seven selected districts in Taiwan, covering both urban and rural areas.
PARTICIPANTS: 4,083 community-dwelling healthy adults aged 55 and older from the Healthy Aging Longitudinal Study.
MEASUREMENTS: A job matrix of work conditions by occupation was generated using data from a representative national survey. Mental demands were assessed by job control and psychological demands from the Job Content Questionnaire, as well as skill levels. Physical demands were assessed using a 4-point Likert scale and dichotomized into high and low levels. Dementia diagnoses were identified based on physician diagnosis registered in the National Health Insurance database.
RESULTS: Over a follow-up period of 6.2 years, 513 participants were diagnosed with dementia. After adjusting for confounding factors in cox regression models, high (vs. low) job control, high -skilled jobs (vs. low), and high physical demands (vs. low) were associated with a reduced future risk of dementia. Psychological demands were not associated with dementia risk.
CONCLUSIONS: Greater utilization of job skills and engagement in physically demanding activities at work may help mitigate the risk of developing dementia. The effects of different dimensions of psychological demands on cognitive health warrant further investigation.
CITATION:
Hang-Ju Yang ; Yun-Chieh Yang ; Chih-Cheng Hsu ; Wan-Ju Cheng (2025): Physical and mental demands of work associated with dementia risk in later life. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100084
A POINT-BASED COGNITIVE IMPAIRMENT SCORING SYSTEM FOR SOUTHEAST ASIAN ADULTS
Wei Ying Tan, Xiangyuan Huang, Caroline Robert, Mervin Tee, Christopher Chen, Gerald Choon Huat Koh, Rob M. van Dam, Nagaendran Kandiah, Saima Hilal
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BACKGROUND: Cognitive impairment is a growing concern in Southeast Asian populations, where the burden of cerebrovascular disease (CeVD) is high. Currently, there is no point-based scoring system for identifying cognitive impairment in these populations.
OBJECTIVE: To develop and validate a simple point-based Cognitive Impairment Scoring System (CISS) for identifying individuals with cognitive impairment no dementia (CIND) and concomitant CeVD in Southeast Asian populations.
DESIGN: A cross-sectional study using data from two population-based studies.
SETTING: Community-based setting in Southeast Asia.
PARTICIPANTS: 1,511 Southeast Asian adults (664 with CIND, 44.0 %).
MEASURES: Two CISS measures were developed: a basic measure including 11 easily assessable risk factors, and an extended measure incorporating seven additional neuroimaging markers. Performance was evaluated using receiver operating characteristic analysis (AUC) and calibration plots.
RESULTS: The AUC for CISS-basic and CISS-extended were 0.81 (95 %CI, 0.76–0.86) and 0.85 (95 %CI, 0.81–0.89), respectively. Calibration plots indicated satisfactory fit for both the basic measure (p=0.82) and the extended measure (p=0.17). The basic measure included age, gender, ethnicity, education, systolic blood pressure, BMI, smoking history, diabetes, hyperlipidemia, stroke history, and mild/moderate depression. The extended measure added neuroimaging markers of CeVD and brain atrophy.
CONCLUSION: The CISS provides a quick, objective, and clinically relevant tool for assessing cognitive impairment risk in Southeast Asian populations. The basic measure is suitable for initial community-based screenings, while the extended measure offers higher specificity for probable diagnosis. This point-based system enables rapid estimation of cognitive status without requiring complex calculations, potentially improving early detection and management of cognitive impairment in clinical practice.
CITATION:
Wei Ying Tan ; Xiangyuan Huang ; Caroline Robert ; Mervin Tee ; Christopher Chen ; Gerald Choon Huat Koh ; Rob M. van Dam ; Nagaendran Kandiah ; Saima Hilal (2025): A point-based cognitive impairment scoring system for southeast Asian adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100069
ASSESSING THE CAUSAL ROLE OF LIPID METABOLITES IN ALZHEIMER\'S DISEASE: A MENDELIAN RANDOMIZATION STUDY
Haoxiang Hu, Jiesheng Mao, Yunhan Zhao, Yihan Zhang, Yihan Zhang, Jiang hai He, Xiaokai Yang
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BACKGROUND: The causal relationship between lipid metabolites and Alzheimer's disease (AD) remains unclear and contradictory. This study aimed to systematically assess the causal relationship between lipid metabolites and AD.
METHODS: A two-step bidirectional Mendelian Randomization (MR) study was employed. The principal analytical technique used to evaluate causation was inverse variance weighting (IVW). Furthermore, mediation analysis was conducted to evaluate the possible function of lipidomes as mediators in the lipid-AD pathway.
RESULTS: Among the 213 lipid metabolites analyzed, significant causal associations with AD were identified Cholesterol esters in large LDL(L-LDL-CE) (OR = 1.236, 95 %CI = 1.052–1.453, P = 0.010), Total cholesterol in large LDL(L-LDL-TC) (OR = 1.506, 95 %CI = 1.235–1.835, P < 0.001), Total cholesterol in medium LDL(M-LDL-TC) (OR = 1.378, 95 %CI = 1.132–1.677, P = 0.001). Mediation analysis further revealed ceramide (d42:2) and phosphatidylinositol (PI) (18:1_18:1) as potential mediators in this relationship.
CONCLUSION: The identification of specific lipid metabolites with causal effects on AD provides new insights into AD pathogenesis and highlights potential targets for preventive strategies.
CITATION:
Haoxiang Hu ; Jiesheng Mao ; Yunhan Zhao ; Yihan Zhang ; Caixiang Zhuang ; Jiang hai He ; Xiaokai Yang (2025): Assessing the causal role of lipid metabolites in Alzheimer's disease: A mendelian randomization study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.10006
INFLUENCE OF APOE Ε4 ON PERFORMANCE OF CSF BIOMARKERS IN DIFFERENTIATING CLINICAL ALZHEIMER\'S DISEASE
Yan Wang, Fangyu Li, Qi Qin, Tingting Li, Qi Wang, Yan Li, Ying Li, Jianping Jia, Alzheimer\'s Disease Neuroimaging Initiative
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INTRODUCTION: Apolipoprotein E ε4 (APOE ε4) bring the higher risk of Alzheimer’ Disease (AD). It is essential to evaluate whether the diagnostic performances and critical values of cerebrospinal fluid (CSF) biomarkers are influenced by APOE ε4, which has guiding significance for the clinical practical application.
METHODS: The differences in CSF biomarkers and their performances between APOE ε4 carriers and non-carriers in distinguishing AD, mild cognitive impairment (MCI) and preclinical AD from normal controls (NCs) were analyzed. The receiver operating characteristic (ROC) curves were generated to compare the area under the curve (AUC) between APOE ε4 carriers and non-carriers, as well as the critical values corresponding Youden Index.
RESULTS: In a cross sectional convenience sample of 1610 participants, lower Aβ42 and Aβ42/Aβ40 and higher p-Tau 181/Aβ42 in CSF were observed among APOE ε4 carriers than non-carriers in NC, MCI, and AD groups (P< 0.05). The performance of CSF p-tau/Aβ42 in distinguishing MCI from NC among APOE ε4 carriers was superior to non-carriers [AUC: 0.714 (95%CI: 0.673- 0.752) vs 0.600 (95%CI: 0.564- 0.634), P< 0.001], although it was similar in distinguishing AD from NC between APOE ε4 carriers and non-carriers [AUC: 0.874 (95%CI: 0.835-0.906) vs 0.876 (95%CI: 0.843- 0.904)]. In the longitudinal cohort of 254 participants, the association of CSF Aβ42, Aβ42/Aβ40 and p-Tau181/Aβ42 with cognitive decline were stronger in APOE ε4 carriers compared to non-carriers (P< 0.05). Meanwhile, the critical values were different depending on APOE genotype.
DISCUSSION: The CSF level of p-Tau181/Aβ42 was significantly different between APOE ε4 carriers and non-carriers at different stages of AD. The results indicate that the performances of CSF biomarkers are influenced by APOE ε4, which should be considered in the practical application.
CITATION:
Yan Wang ; Fangyu Li ; Qi Qin ; Tingting Li ; Qi Wang ; Yan Li ; Ying Li ; Jianping Jia ; Alzheimer's Disease Neuroimaging Initiative (2025): Influence of APOE ε4 on performance of CSF biomarkers in differentiating clinical Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100065
EFFECTS OF TRADITIONAL THAI FOLK DANCE COMBINED WITH COGNITIVE STIMULATION PROGRAM ON BEHAVIOR AND COGNITION AMONG OLDER ADULTS WITH COGNITIVE DECLINE: A RANDOMIZED CONTROLLED TRIAL
Panawat Sanprakhon, Wachira Suriyawong, Natsala Longphasuk, Natsuda Khatichop, Churai Arpaichiraratana, Sresuda Wongwiseskul, Peerayut Rattanaselanon, Noppamas Pipatpiboon, Papan Thaipisuttikul
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BACKGROUND: Older adults with mild behavioral impairment (MBI) are at the higher risk of developing dementia compared to those without MBI, leading to decreased quality of life (QoL). Addressing MBI in older adults provides valuable opportunities to prevent dementia.
OBJECTIVES: This study aimed to determine the effects of traditional Thai folk dance combined with a cognitive stimulation program on MBI, QoL, subjective cognitive decline (SCD), and cognitive functioning in older Thai adults.
DESIGN: Single-blinded, two-armed, randomized controlled trial, with a three-month follow-up period.
SETTING: Outpatient chronic disease clinics at two districts in Suphan Buri province, Thailand.
PARTICIPANTS: One-hundred twenty-eight older adults with MBI were randomly assigned to either the experimental (n = 64) and cognitive education control group (n = 64).
INTERVENTION: The 14-session, 7-week traditional Thai folk-dance program combined with cognitive stimulation focused on enhanced moderate intensity physical activity and cognitive stimulation engagement to improve MBI of older adults.
MEASUREMENTS: The primary outcome was MBI assessed using Mild Behavioral Impairment Checklist. Secondary outcomes were QoL, SCD, and cognitive tests of memory and executive functions.
RESULTS: Compared to the control group, participants in the experimental group demonstrated significantly reduced MBI (p <.01), improved QoL (p <.01), decreased SCD (p <.01), and enhanced cognitive functioning (p <.01) after the 7-week intervention and at the 12-week follow-up.
CONCLUSION: The traditional Thai folk dance combined with cognitive stimulation improved outcomes related to early signs of dementia and enhanced the overall QoL of older adults.
CITATION:
Panawat Sanprakhon ; Wachira Suriyawong ; Natsala Longphasuk ; Natsuda Khatichop ; Churai Arpaichiraratana ; Sresuda Wongwiseskul ; Peerayut Rattanaselanon ; Noppamas Pipatpiboon ; Papan Thaipisuttikul (2025): Effects of traditional Thai folk dance combined with cognitive stimulation program on behavior and cognition among older adults with cognitive decline: A randomized controlled trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100066
CUTTING THROUGH THE NOISE: A NARRATIVE REVIEW OF ALZHEIMER\'S DISEASE PLASMA BIOMARKERS FOR ROUTINE CLINICAL USE
M. Schöll, A. Vrillon, T. Ikeuchi, F.C. Quevenco, L. Iaccarino, S.Z. Vasileva-Metodiev, S.C. Burnham, J. Hendrix, S. Epelbaum, H. Zetterberg, S. Palmqvist
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As novel, anti-amyloid therapies have become more widely available, access to timely and accurate diagnosis has become integral to ensuring optimal treatment of patients with early-stage Alzheimer's disease (AD). Plasma biomarkers are a promising tool for identifying AD pathology; however, several technical and clinical factors need to be considered prior to their implementation in routine clinical use. Given the rapid pace of advancements in the field and the wide array of available biomarkers and tests, this review aims to summarize these considerations, evaluate available platforms, and discuss the steps needed to bring plasma biomarker testing to the clinic. We focus on plasma phosphorylated(p)-tau, specifically plasma p-tau217, as a robust candidate across both primary and secondary care settings.
Despite the high performance and robustness demonstrated in research, plasma p-tau217, like all plasma biomarkers, can be affected by analytical and pre-analytical variability as well as patient comorbidities, sex, ethnicity, and race. This review also discusses the advantages of the two-point cut-off approach to mitigating these factors, and the challenges raised by the resulting intermediate range measurements, where clinical guidance is still unclear. Further validation of plasma p-tau217 in heterogeneous, real-world cohorts will help to increase confidence in testing and support establishing a standardized approach.
Plasma biomarkers are poised to become a more affordable and less invasive alternative to PET and CSF testing. However, understanding the factors that impact plasma biomarker measurement and interpretation is critical prior to their implementation in routine clinical use.
CITATION:
M. Schöll ; A. Vrillon ; T. Ikeuchi ; F.C. Quevenco ; L. Iaccarino ; S.Z. Vasileva-Metodiev ; S.C. Burnham ; J. Hendrix ; S. Epelbaum ; H. Zetterberg ; S. Palmqvist (2025): Cutting through the noise: A narrative review of Alzheimer's disease plasma biomarkers for routine clinical use. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100056
ASSOCIATION BETWEEN L-Α GLYCERYLPHOSPHORYLCHOLINE USE AND DELAYED DEMENTIA CONVERSION: A NATIONWIDE LONGITUDINAL STUDY IN SOUTH KOREA
Han-Kyeol Kim, Sojeong Park, Sung-Woo Kim, Eun Seok Park, Jin Yong Hong, Ickpyo Hong, Min Seok Baek
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BACKGROUND: Alzheimer's disease and vascular dementia are two of the most common causes of dementia. While early diagnosis and intervention are crucial, available treatments and research concerning the mild cognitive impairment stage remain limited. This study aimed to evaluate the real-world effectiveness and safety of L-α glycerylphosphorylcholine in this context.
OBJECTIVES: To investigate the impact of L-α glycerylphosphorylcholine on the risk of conversion from mild cognitive impairment to Alzheimer's disease dementia and vascular dementia, as well as its influence on stroke risk.
DESIGN: A nationwide, population-based cohort study.
SETTING: Data from South Korea's National Health Insurance Service.
PARTICIPANTS: Overall, 508,107 patients newly diagnosed with mild cognitive impairment between 2013 and 2016 were included.
INTERVENTION: Patients were classified as users or non-users of L-α glycerylphosphorylcholine based on prescription records.
MEASUREMENTS: The primary outcomes were the risk of progression to Alzheimer's disease dementia and vascular dementia. Stroke risk was examined as a secondary outcome. A time-dependent Cox regression analysis was used to adjust for demographic and clinical factors.
RESULTS: Compared to non-users, L-α glycerylphosphorylcholine users had a lower risk of progression to Alzheimer's disease dementia (hazard ratio = 0.899, 95 % confidence interval: 0.882–0.918) and vascular dementia (hazard ratio = 0.832, 95 % confidence interval: 0.801–0.865) within 2,435,924 and 662,281.6 person-years, respectively. In patients under 65, L-α glycerylphosphorylcholine significantly reduced the risk of progression to Alzheimer's and vascular dementia. Stroke risk significantly decreased in patients who did not progress to dementia but not in those who did.
CONCLUSIONS: L-α Glycerylphosphorylcholine reduces dementia conversion and stroke risk in patients with mild cognitive impairment, making it a viable early intervention. Future large-scale randomized controlled studies should examine its effects on other dementia subtypes and long-term cognitive outcomes.
CITATION:
Han-Kyeol Kim ; Sojeong Park ; Sung-Woo Kim ; Eun Seok Park ; Jin Yong Hong ; Ickpyo Hong ; Min Seok Baek (2025): Association between L-α glycerylphosphorylcholine use and delayed dementia conversion: A nationwide longitudinal study in South Korea. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100059
THE ASSOCIATIONS BETWEEN FRESH VEGETABLE AND FRUIT CONSUMPTION AND PLASMA AND PET BIOMARKERS IN PRECLINICAL ALZHEIMER\'S DISEASE: A CROSS-SECTIONAL AND LONGITUDINAL STUDY OF CHINESE POPULATION
Heling Chu, Chuyi Huang, Fang Xie, Qihao Guo
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BACKGROUND: The identification of the modifiable lifestyle factors including dietary habits in older adults of preclinical Alzheimer's disease (AD) and early effective interventions are of great importance.
OBJECTIVES: We studied whether the consumption of fresh vegetables and fruits was different between cognitively unimpaired (CU) and cognitively impaired (CI) population and mainly investigated the associations between vegetable and fruit consumption and PET and plasma AD biomarkers in older CU adults with higher β-amyloid (Aβ) burden.
DESIGN, SETTING, AND PARTICIPANTS: Older adults with the age of 50–85 years were enrolled for a cross-sectional and longitudinal study. The groups depended on whether the participants were CU or CI. Partial participants whose habits remained unchanged were followed up.
MEASUREMENTS: The consumption data of vegetables and fruits were collected using a validated self-reported questionnaire. We mainly investigated the associations between vegetable and fruit consumption and various biomarkers in CU participants with positive 18F-florbetapir PET scan (Aβ-PET), part of whom also underwent plasma AD biomarkers tests and 18F-MK6240 PET scan (tau-PET). Correlation and multiple linear regression analyses were used to investigate the associations between vegetable and fruit consumption and AD biomarkers.
RESULTS: A total of 1433 participants were enrolled, of which CU accounted for 49.4 %. Most of the intake habits of vegetables and fruits was different between CU and CI participants. 177 CU participants with Aβ-PET positive were selected for the following study. Multiple linear regression analysis showed higher consumption of fresh vegetables (>200 g/d), dark vegetables (>100 g/d, ≥2d/week), fruits (>100 g/d), berries (>100 g/d) and grapes (>100 g/d) more or less had associations with the plasma biomarkers including Aβ40, t-Tau, p-Tau-181 and neurofilament light chain as well as amyloid and Tau PET biomarkers. Most of the habits were associated with the change of cognitive function after an approximately two-year follow-up. Especially, higher intakes of fruits and grapes correlated with both lower Aβ and Tau burden and inversely with cognitive decline after follow-up.
CONCLUSION: Our data indicates that higher consumption of vegetables, dark vegetables, fruits, berries and grapes is associated with amyloid and Tau PET and plasma biomarkers in preclinical AD participants and the changes of cognitive function after follow-up. Higher intakes of fruits (>100 g/d) and grapes (>100 g/d) may be more helpful for reducing the risk of AD development.
CITATION:
Heling Chu ; Chuyi Huang ; Fang Xie ; Qihao Guo (2025): The associations between fresh vegetable and fruit consumption and plasma and PET biomarkers in preclinical Alzheimer's disease: A cross-sectional and longitudinal study of Chinese population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100076
JPAD Volume 12, N°03 - 2025
EDITORIAL: VISION, COURAGE, AND ACADEMIC FREEDOM
Bruno Vellas
J Prev Alz Dis 2025;3(12)
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CITATION:
Bruno Vellas (2025): Vision, courage, and academic freedom. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100095
VALIDATION OF THE MULTI-DAY BOSTON REMOTE ASSESSMENT OF NEUROCOGNITIVE HEALTH (BRANCH) AMONG COGNITIVELY IMPAIRED & UNIMPAIRED OLDER ADULTS
Emma L. Weizenbaum, Stephanie Hsieh, Cassidy Molinare, Daniel Soberanes, Caitlyn Christiano, Andrea??M? Román Viera, Juliana A.U. Anzai, Stephanie Moreno, Emily C. Campbell, Hyun-Sik Yang, Gad A. Marshall, Reisa A. Sperling, Kathryn V. Papp, Rebecca E. Amariglio
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: The multi-day Boston Remote Assessment of Neurocognitive Health (BRANCH) is a remote, web-based assessment designed to capture the earliest cognitive changes in the preclinical stage of Alzheimer's disease (AD). It has been validated in unimpaired older adults, but as individuals progress on the AD continuum, assessments need to remain feasible and valid at different clinical stages. The focus of this study was to assess feasibility and validity of multi-day BRANCH in participants with and without cognitive impairment.
METHODS: For seven days participants completed the BRANCH paradigm to capture a muti-day learning curve score. Participants also completed the mini-mental-status-exam (MMSE) and the Quick Dementia Rating Scale (QDRS). The primary cohort included 81 older adults: 38 with cognitive impairment (CI) and 43 cognitively-unimpaired (CU). A complementary replication cohort included 16 participants with consensus-defined mild cognitive impairment (MCI) and 47 demographically-matched cognitively unimpaired participants.
RESULTS: Multi-day BRANCH was feasibile with 92 % or participants completing all seven days of testing. More CI than CU reported nervousness and found tasks slightly less enjoyable on Day 1, but ratings increased at a similar rate in both groups. Convergent validity was confirmed by a positive association between BRANCH and total MMSE and QDRS scores. There was a large effect size of group status on BRANCH (CI vs. CU; Cohen's d = 0.83) and per logistic regression, BRANCH significantly predicted group status (β = -1.49, p < 0.001); even more so between MCI and CU in the replication cohort.
CONCLUSIONS: Findings suggest that a remotely administered web-based assessment of multi-day learning is feasible and valid in participants with and without cognitive impairment.
CITATION:
Emma L. Weizenbaum ; Stephanie Hsieh ; Cassidy Molinare ; Daniel Soberanes ; Caitlyn Christiano ; Andrea M․ Román Viera ; Juliana A.U. Anzai ; Stephanie Moreno ; Emily C. Campbell ; Hyun-Sik Yang ; Gad A. Marshall ; Reisa A. Sperling ; Kathryn V. Papp ; Rebecca E. Amariglio (2025): Validation of the multi-day Boston remote assessment of neurocognitive health (BRANCH) among cognitively impaired & unimpaired older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100057
MEMSCREEN: A SMARTPHONE APPLICATION FOR DETECTION OF MILD COGNITIVE IMPAIRMENT: A VALIDATION STUDY: SMARTPHONE APP FOR MCI DETECTION
Julien Dumurgier, Claire Paquet, Jacques Hugon, Vincent Planche, Sinead Gaubert, Stéphane Epelbaum, Stéphanie Bombois, Marc Teichmann, Richard Levy, Estelle Baudouin, Agathe Vrillon, Claire Hourrègue, Emmanuel Cognat, Séverine Sabia, Archana Singh-Manoux
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Primary care is often the first point of contact for patients with cognitive complaints, making initial cognitive screening an essential step to avoid delays in diagnosing Alzheimer's disease (AD) at an early stage. We developed MemScreen, a self-administered smartphone application that assesses overall cognition and verbal memory, and evaluated its ability to detect mild cognitive impairment (MCI) in both general and clinical populations.
METHODS: We conducted two validation cohort studies: (1) UK-based Whitehall II cohort study (13th wave, 2018–2022) involving a general population (MCI defined by poor performance on a global cognitive score), and (2) five French memory clinics involving patients without dementia (amnestic MCI defined by the Free and Cued Selective Reminding Test). MemScreen, MMSE, and TMT-A effectiveness was assessed using Area Under the Curve (AUC) values from unadjusted and adjusted logistic regression models.
RESULTS: In Whitehall II (n = 2118, mean age 75.9 years, 23.9 % women, 14.5 % MCI), median MemScreen completion time was 4 min 18 s. MemScreen had the highest AUC (0.87; 95 % CI: 0.82–0.89) for distinguishing MCI, outperforming MMSE (AUC = 0.79; 0.76–0.82; p = 0.018) and TMT-A (AUC = 0.77; 0.74–0.80; p = 0.023). MemScreen sensitivity and specificity were 78.6 % and 78.7 %, respectively. In memory clinics (n = 303, mean age 70.5 years, 53 % women, 46.9 % amnestic MCI), median completion time was 5 min 17 s. MemScreen showed superior performance (AUC = 0.87; 0.83–0.91) compared to MMSE (AUC = 0.72; 0.67–0.78; p < 0.001) and TMT-A (AUC = 0.63; 0.56–0.69; p < 0.001), with 93.0 % sensitivity and 54.0 % specificity for amnestic MCI.
DISCUSSION: MemScreen outperformed traditional tests in identifying MCI in both general and clinical populations. Its self-administration and short completion time suggest potential as an effective screening tool to optimize memory clinic referrals for AD diagnosis and treatment.
CITATION:
Julien Dumurgier ; Claire Paquet ; Jacques Hugon ; Vincent Planche ; Sinead Gaubert ; Stéphane Epelbaum ; Stéphanie Bombois ; Marc Teichmann ; Richard Levy ; Estelle Baudouin ; Agathe Vrillon ; Claire Hourrègue ; Emmanuel Cognat ; Séverine Sabia ; Archana Singh-Manoux (2025): MemScreen: A smartphone application for detection of mild cognitive impairment: A validation study: Smartphone App for MCI Detection. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100077
EFFECTIVENESS OF DIGITAL SCREENING TOOLS IN DETECTING COGNITIVE IMPAIRMENT AMONG COMMUNITY-DWELLING ELDERLY IN NORTHERN CHINA: A LARGE COHORT STUDY
Xiaonan Zhang, Feifei Zhang, Sijia Hou, Chenxi Hao, Xiangmin Fan, Yarong Zhao, Wenjing Bao, Junpin An, Shuning Du, Guowen Min, Qiuyan Wang, Wencheng Zhu, Yang Li, Hui Zhang
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryINTRODUCTION: This study assessed the effectiveness of three digital screening tools in detecting cognitive impairment (CI) in a large cohort of community-dwelling elderly individuals and investigated the relationship between key digital features and plasma p-tau217 levels.
METHODS: This community-based cohort study included 1,083 participants aged 65 years or older, with 337 diagnosed with CI and 746 classified as normal controls (NC). We utilized two screening approaches: traditional methods (AD8, MMSE scale, and APOE genotyping) and digital tools (drawing, gait, and eye tracking). LightGBM-based machine learning models were developed for each digital screening tool and their combination, and their performance was evaluated. The correlation between key digital features and plasma p-tau217 levels was analyzed as well.
RESULTS: A total of 21 drawing, 71 gait, and 35 eye-tracking parameters showed significant differences between the two groups (all p < 0.05). The area under the curve (AUC) values for the drawing, gait, and eye-tracking models in distinguishing CI from NC were 0.860, 0.848, and 0.895, respectively. The combination of eye-tracking and drawing achieved the highest classification effectiveness, with an AUC of 0.958, and accuracy, sensitivity, and specificity all exceeded 85%. The fusion model achieved an AUC of 0.928 in distinguishing mild cognitive impairment (MCI) from NC. Additionally, several digital features (including two drawing, ten gait, and one eye-tracking parameters) were significantly correlated with plasma p-tau217 levels (all |r| > 0.3, p < 0.001).
DISCUSSION: Digital screening tools offer objective, accurate, and efficient alternatives for detecting CI in community settings, with the fusion of drawing and eye-tracking providing the best performance (AUC = 0.958).
CITATION:
Xiaonan Zhang ; Feifei Zhang ; Sijia Hou ; Chenxi Hao ; Xiangmin Fan ; Yarong Zhao ; Wenjing Bao ; Junpin An ; Shuning Du ; Guowen Min ; Qiuyan Wang ; Wencheng Zhu ; Yang Li ; Hui Zhang (2025): Effectiveness of digital screening tools in detecting cognitive impairment among community-dwelling elderly in Northern China: A large cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100080
BRAIN HEALTH CLINICS – AN EVOLVING CLINICAL PATHWAY?
Anneka F. Butters, Jonathan Blackman, Hannah Farouk, Saba Meky, Margaret A. Newson, Tomas Lemke, Natalie Rosewell, James A. Selwood, Nicholas L. Turner, Elizabeth J. Coulthard, Hilary A. Archer
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: Dementia clinics traditionally focus on diagnosis and post-diagnostic care. Awareness is increasing that attention to risk factors and their prevention also forms a key part of dementia management.
OBJECTIVES: To describe our Bristol Brain Health clinic including 1) Clinical pathway 2) Patient population 3) Patient experience 4) Evaluation in line with published gold standards.
DESIGN/ SETTING: Observational, (longitudinal/retrospective) clinical cohort study of patients attending the North Bristol NHS Trust's Brain Health Service.
PARTICIPANTS: One-hundred and ten patients with mild cognitive disorders attending clinic between 2017- 2023.
MEASUREMENTS: We collected data from medical records including clinical assessments, cerebrospinal fluid (CSF) for biomarkers of Alzheimer's Disease (AD), and a lifestyle questionnaire. Descriptive statistics were performed and a clinic evaluation was carried out using recommendations from The European Task Force for Brain Health Services.
RESULTS: Average age was 63.9 years (SD: 11.2). 74 patients were male (62.8 %). The mean baseline Montreal Cognitive Assessment (MoCA) score was 24.4 (SD: 3.6). 73 patients (66.4 %) received a preventative lifestyle intervention with a review of risk and protective factors for dementia, and development of a bespoke risk reduction plan. Commonly identified risk factors; low mood; n = 61 (55.5 %), hypertension; n = 54 (49.1 %), high cholesterol; n = 42 (47.3 %), and hearing loss; n = 44 (40 %). CSF testing for AD was carried out in 38 individuals and was positive in 17 cases. At last review, one fifth of patients had progressed to dementia. Most common diagnoses; AD; n = 22 (20 %), Functional Cognitive Disorder; n = 16 (14.6 %), Vascular; n = 8 (7.3 %). Patient feedback was good, with all responders recommending the clinic and more than three-quarters of patients being ‘extremely likely” to. Clinic evaluation highlighted ‘Risk Assessment’ and ‘Personalised Intervention’ as brain health pillar strengths. ‘Cognitive Enhancement’ was an area for further development.
CONCLUSIONS: Our patients had access to a range of cutting-edge, diagnostic assessments, in addition to a preventative lifestyle intervention. Our population had a high rate of dementia risk factors and a heterogeneous range of diagnoses. CSF biomarker testing was helpful for differentiating between those with early AD, and others with a multi-factorial presentation. The attendance rates for our preventative intervention suggests patients are receptive to taking a proactive approach to managing risk. This population merits further investigation and continued targeting with preventative measures.
CITATION:
Anneka F․ Butters ; Jonathan Blackman ; Hannah Farouk ; Saba Meky ; Margaret․ A Newson ; Tomas Lemke ; Natalie Rosewell ; James․ A․ Selwood ; Nicholas․ L․ Turner ; Elizabeth․ J․ Coulthard ; Hilary․ A․ Archer (2025): Brain health clinics – An evolving clinical pathway?. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100051
TAILORING IMPLEMENTATION STRATEGIES FOR THE HEALTHY ACTIONS AND LIFESTYLES TO AVOID DEMENTIA OR HISPANOS Y EL ALTO A LA DEMENCIA PROGRAM: LESSONS LEARNED FROM A SURVEY STUDY
Sara Moukarzel, Carlos E.E. Araujo-Menendez, Eliza Galang, Zvinka Z. Zlatar, Howard H. Feldman, Sarah J. Banks, HALT-AD Study Group
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: Healthy Actions and Lifestyles to Avoid Dementia Program (HALT-AD) or Hispanos y el ALTo a la Demencia is a recently-developed online educational platform to help individuals identify and modify their own dementia modifiable risk factors (MRF). In light of known challenges in recruiting and retaining diverse participants in research studies, there is a need to identify data-informed strategies that will contribute to effective outreach and tailored implementation of HALT-AD among its intended users of Hispanic and non-Hispanic midlife and older adults in the US.
OBJECTIVES: To identify factors (i.e, demographic, medical, psychosocial and environmental) that may facilitate or impede effective program enrollment and participation.
DESIGN: Cross-sectional study.
SETTING: Data from an online and self-administered survey conducted between January and April 2023.
PARTICIPANTS: Residents of California, predominately San Diego, who were 50 to 85 years old, with no dementia or Alzheimer's disease, proficient in English or Spanish and with enough technical ability to complete the survey electronically (n=157; 43% Hispanic).
INTERVENTION (if any): none.
MEASUREMENTS: RedCap was used to capture answers to closed and open-ended survey questions. Mixed-methods analysis was used: For quantitative data, descriptive statistics, comparisons by group (Hispanic/non-Hispanic), and exploratory factor analysis were conducted in SPSS. Thematic analysis with open coding in Excel was used for qualitative responses.
RESULTS: Independent of ethnicity, participants’ most preferred method of reach for recruitment was through a conversation with their doctor or with a family member or friend. Their least preferred method was receiving a Facebook advertisement especially among non-Hispanics. Interest in program participation did not differ by sociodemographic characteristics or self-rated satisfaction with individualized MRFs. Instead, having higher confidence in one's ability to commit to behavior change was significantly associated with higher interest in program participation. While a common theme to motivate both groups to participate was the potential to decrease dementia risk, non-Hispanics were motivated by the premise of supporting research and having a positive user experience. For program implementation, Hispanics were more likely to be interested in participating if live sessions, either online or in-person, were provided to offer support with making lifestyle changes as adjunct to completing online courses independently. In both groups, participation may be further facilitated by offering wearable devices which provide participants with feedback on lifestyle change progress.
CONCLUSIONS: A “one-size-fits-all” approach to recruitment and implementation of HALT-AD may not be effective in enrolling and retaining participants in future studies or for clinical use. Instead, a tailored approach that accounts for personal and ethnically-dependent preferences may be more beneficial.
CITATION:
Sara Moukarzel ; Carlos E.E. Araujo-Menendez ; Eliza Galang ; Zvinka Z. Zlatar ; Howard H. Feldman ; Sarah J. Banks ; HALT-AD Study Group (2025): Tailoring implementation strategies for the healthy actions and lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia Program: Lessons learned from a survey study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100053
EFFECT OF A SINGLE NONPHARMACOLOGICAL INTERVENTION ON COGNITIVE FUNCTIONING IN OLDER ADULTS WITH MILD-TO-MODERATE ALZHEIMER\'S DISEASE: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS: NON-DRUG INTERVENTIONS FOR ALZHEIMER\'S DISEASE
Kejin Chen, Xiaoyan Zhao, Jingwen Zhou
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryMost studies of nonpharmacological interventions have used a combination of medications in experimental and control groups to improve cognitive functioning or to control symptoms, but the results have been inconsistent with respect to the effects of single nonpharmacological interventions on cognitive functioning in older patients with Alzheimer's disease. The aim of this study was to assess the effect of a single nonpharmacological intervention on cognitive functioning in older adults with mild-to-moderate Alzheimer's disease. We conducted a systematic review and meta-analysis in the first week of January 2024, searching eight electronic databases for articles that reflect on non-pharmacological interventions in Alzheimer's disease published between January 1, 1986, and December 31, 2023. All included articles had to be randomized controlled trials. The primary measure was the change in cognitive function before and after the intervention. Data were extracted by two authors and quality was assessed using the Cochrane Handbook. With the exception of the Montreal Cognitive Assessment (MoCA) scale [MD=2.99, 95% CI (-0.66,6.63)], the differences between the intervention group and the control group were significant for all the remaining scales, namely, the Mini-Mental State Examination (MMSE) [SMD=0.65, 95% CI (0.15,1.15)], Activity of Daily Living Scale (ADL) [MD=-2.30, 95% CI (-3.63,0.97)], Quality of Life in Alzheimer's Disease Scale (QoL-AD) [MD=5.03, 95% CI (2.27,7.78)], Neuropsychiatric Inventory (NPI) [MD=-2.16, 95% CI (-3.86,0.46)], and Alzheimer's Disease Assessment Scale-cognitive score (ADAS-cog) [MD=-5.21, 95% CI (-7.89,2.54)]. Subgroup analysis revealed that the most effective intervention was exercise therapy, followed by repetitive transcranial magnetic stimulation. On the other hand, music therapy was not found to be effective. Current evidence suggests that nonpharmacological interventions can be used to improve cognitive functioning in older adults with mild-to-moderate Alzheimer's disease. This study was registered in PROSPERO (registration number: CRD42024497247).
CITATION:
Kejin Chen ; Xiaoyan Zhao ; Jingwen Zhou (2025): Effect of a single nonpharmacological intervention on cognitive functioning in older adults with mild-to-moderate Alzheimer's disease: A meta-analysis of randomized controlled trials: non-drug interventions for Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100050
SOCIAL ISOLATION, LONELINESS, AND THEIR JOINT EFFECTS ON COGNITIVE DECLINE AND INCIDENT ALZHEIMER\'S DISEASE: FINDINGS FROM THE CHICAGO HEALTH AND AGING PROJECT
Ted K.S. Ng, Todd Beck, Kyle R. Dennis, Pankaja Desai, Kristin Krueger, Klodian Dhana, Robert S. Wilson, Denis A. Evans, Kumar B. Rajan
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: There has been contradictory evidence on the prospective associations between social isolation/loneliness (SI/L) and cognitive decline (CD). There is also a scarcity of large and diverse population-based cohort studies examining SI/L that have confirmed clinical diagnoses of Alzheimer's Disease (AD). Notably, beyond individual associations, whether the effects of SI/L compound and accelerate CD and incident AD are not known.
OBJECTIVES: We hypothesized that SI and L, independently, would be associated with CD and incident AD to a similar extent, and the association of SI with CD and incident AD would be higher in lonely older adults.
DESIGN: Prospective cohort study.
SETTING: Urban Chicago areas.
PARTICIPANTS: We analyzed data in the Chicago Health and Aging Project (CHAP), which comprised 7,760 biracial community-dwelling older adults [mean age (standard deviation (SD))=72.3 (6.3); 64 % Black & 63 % women; mean (SD) of follow-up=7.9 (4.3) years].
INTERVENTION (if any): NA.
MEASUREMENTS: Linear mixed and logistic regression models were used to regress CD and incident AD separately on the SI index/L.
RESULTS: SI index and L were significantly associated with CD, with one-point increase of beta estimate (SE, p-value) = -0.002 (0.001,0.022) and -0.012 (0.003,<0.001), respectively. Given that the SI index ranges from 0 to 5 and the L from 0 to 1, they had similar effect sizes. Similarly, there were significant associations between SI index and incident AD, odds ratio (95 % CI, p-value) = 1.183 (1.016–1.379,0.029), and between L and incident AD, 2.117 (1.227–3.655,0.006). When stratified by loneliness status, compared to older adults who were not isolated and not lonely, older adults who reported being socially isolated and not lonely experienced accelerated CD, -0.003 (0.001,0.004), despite no significantly increased odds of incident AD.
CONCLUSIONS: SI/L had significant associations with CD and incident AD. Notably, socially isolated older adults who reported not being lonely appeared to be most socially vulnerable to CD. These findings suggest a specific at-risk subgroup of socially vulnerable older adults for future targeted interventions to improve cognitive health.
CITATION:
Ted K.S. Ng ; Todd Beck ; Kyle R. Dennis ; Pankaja Desai ; Kristin Krueger ; Klodian Dhana ; Robert S. Wilson ; Denis A. Evans ; Kumar B. Rajan (2025): Social isolation, loneliness, and their joint effects on cognitive decline and incident Alzheimer's disease: Findings from the Chicago health and aging project. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100046
USE OF LECANEMAB AND DONANEMAB IN THE CANADIAN HEALTHCARE SYSTEM: EVIDENCE, CHALLENGES, AND AREAS FOR FUTURE RESEARCH
Eric E. Smith, Natalie A. Phillips, Howard H. Feldman, Michael Borrie, Aravind Ganesh, Alexandre Henri-Bhargava, Philippe Desmarais, Andrew Frank, AmanPreet Badhwar, Laura Barlow, Robert Bartha, Sarah Best, Jennifer Bethell, Jaspreet Bhangu, Sandra E. Black, Christian Bocti, Susan E. Bronskill, Amer M. Burhan, Frederic Calon, Richard Camicioli, Howard Chertkow
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryLecanemab and donanemab are monoclonal antibody therapies that remove amyloid-beta from the brain. They are the first therapies that alter a fundamental mechanism, amyloid-beta deposition, in Alzheimer disease (AD). To inform Canadian decisions on approval and use of these drugs, the Canadian Consortium on Neurodegeneration in Aging commissioned Work Groups to review evidence on the efficacy and safety of these new therapies, as well as their projected impacts on Canadian dementia systems of care. We included persons with lived experience with Alzheimer disease in the discussion about the benefits and harms. Our review of the trial publications found high quality evidence of statistically significant group differences, but also recognized that there are mixed views on the clinical relevance of the observed differences and the value of therapy for individual patients. The drugs are intended for persons with early AD, at a stage of mild cognitive impairment or mild dementia. If patients are treated, then confirmation of AD by positron emission tomography or cerebrospinal fluid analysis and monitoring for risk of amyloid-related imaging abnormalities was recommended, as done in the clinical trials, although it would strain Canadian resource capacity. More data are needed to determine the size of the potentially eligible treatment population in Canada.
CITATION:
Eric E. Smith ; Natalie A. Phillips ; Howard H. Feldman ; Michael Borrie ; Aravind Ganesh ; Alexandre Henri-Bhargava ; Philippe Desmarais ; Andrew Frank ; AmanPreet Badhwar ; Laura Barlow ; Robert Bartha ; Sarah Best ; Jennifer Bethell ; Jaspreet Bhangu ; Sandra E. Black ; Christian Bocti ; Susan E. Bronskill ; Amer M. Burhan ; Frederic Calon ; Richard Camicioli ; Howard Chertkow (2025): Use of lecanemab and donanemab in the Canadian healthcare system: Evidence, challenges, and areas for future research. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100068
AMERICAN\'S OVERALL AND EQUITY-BASED SOCIETAL VALUATION OF A DISEASE-MODIFYING ALZHEIMER\'S TREATMENT: RESULTS FROM A DISCRETE CHOICE EXPERIMENT
Francisco Perez-Arce, Jeremy Burke, Lila Rabinovich, Quanwu Zhang, Amir Abbas Tahami Monfared, Soeren Mattke
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryOBJECTIVES: To estimate Americans’ willingness-to-pay (WTP) for universal access to a disease-modifying Alzheimer's disease (AD) treatment with a discrete choice experiment in a nationally representative sample. As part of this experiment, we examined whether providing information about the higher disease burden among minorities and persons of lower socioeconomic status (SES) changes WTP.
METHODS: We conducted an information experiment using the nationally representative Understanding America Study (UAS) panel. Participants were provided with general information about AD and a hypothetical treatment that reduces disease progression by 30 %. Two-thirds of the sample were randomized to receive additional information about the higher prevalence of Alzheimer's among either lower SES groups or racial/ethnic minorities. We measured participants' WTP for making the treatment nationally available as a fixed annual fee and income-proportionate fee. Differences in WTP between those exposed to the additional information and those who were not provide the societal valuation of the equity-enhancing effects of the AD treatment.
RESULTS: Average valuations were $252, $260 and $247 per year, and 0.59 %, 0.59 % and 0.61 % of earned income, for the control, race/ethnicity and SES frames, respectively—all statistically indistinguishable. These average results imply that Americans would be willing to pay $33.7 billion based on the fixed fee and $51.4 billion based on the income-related charge for universal access to an AD treatment annually, but their valuation does not further increase when informed about equity considerations.
CONCLUSIONS: While Americans value universal access to an AD treatment highly, health equity considerations did not significantly alter respondents’ WTP.
CITATION:
Francisco Perez-Arce ; Jeremy Burke ; Lila Rabinovich ; Quanwu Zhang ; Amir Abbas Tahami Monfared ; Soeren Mattke (2025): American's overall and equity-based societal valuation of a disease-modifying Alzheimer's treatment: Results from a discrete choice experiment. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100036
EFFECTS OF THE DAVOS ALZHEIMER\'S COLLABORATIVE EARLY DETECTION OF COGNITIVE IMPAIRMENT PROGRAM ON CLINICIAN ATTITUDES, ENGAGEMENT, AND CONFIDENCE
Tabasa Ozawa, Katherine J. Selzler, Daniel E. Ball, Amy Deckert, Tim MacLeod, Otelo Corrêa dos Santos Filho, Ishtar Govia, Janelle N. Robinson, Hisatomo Kowa, Mariana Lopez-Ortega, Alison McKean, Wendy Chambers, Steven R. Smith, Magda Baksh, Deanna R. Willis, Nicole R. Fowler, Soeren Mattke, The DAC Consortium
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: The number of people with dementia is expected to grow substantially across the world due to population aging, but cognitive impairment remains undetected and undiagnosed, especially in early stages. Newly available diagnostic tools such as digital cognitive assessments and blood biomarker tests may be well suited to increase the rates of early detection of dementia in primary care.
OBJECTIVES: The objective of the Davos Alzheimer's Collaborative Healthcare System Preparedness (DAC-SP) Early Detection Flagship Program was to improve the rate of early detection of cognitive impairment in primary care and non-specialty settings. We aimed to understand the program's impact on clinician attitudes, engagement, and confidence in diagnosing and managing cognitive impairment.
DESIGN: Survey of participating healthcare professionals before and after the intervention.
SETTING: The DAC Healthcare System Preparedness Early Detection Flagship Program was implemented in seven sites across six countries: Brazil, Jamaica, Japan, Mexico, Scotland, and the United States (2 sites).
PARTICIPANTS: 110 healthcare professionals, including, primary care physicians, specialists (neurologists and psychologists), nurses, nurse practitioners, physician assistants, social workers, and healthcare support workers completed the pre-intervention survey. 68 healthcare professionals completed the post-intervention survey.
INTERVENTION: Participating sites implemented a digital cognitive assessment tool and a blood biomarker test for the Alzheimer's pathology and were trained in the administration of the digital cognitive assessment tool. The intervention was adapted to each site for cultural relevance and operational feasibility.
MEASUREMENTS: Participants completed the General Practitioners Attitude and Confidence Scale for Dementia (GPACS-D), a 15-item scale with three subscales: Attitude to Care (six items), Confidence in Clinical Abilities (six items), and Engagement (three items). In addition to the subscale scores, the total GPACS-D score was reported.
RESULTS: Across all sites, there was a significant increase in the Confidence in Clinical Abilities score from 2.98 (SD = 0.77) pre-intervention to 3.27 (SD = 0.72) post-intervention (p = 0.01), and in the total GPACS-D score from 3.48 (SD = 0.48) to 3.65 (SD = 0.39) (p = 0.01). There were non-significant increases in the Attitude to Care and Engagement scores across all sites.
CONCLUSIONS: The implementation of digital cognitive assessment tools and a blood biomarker test was associated with an increase in healthcare professionals’ confidence in diagnosing and managing patients with cognitive impairment in primary care and non-specialty settings. Digital cognitive assessments and blood biomarker tests are promising tools that could be utilized in primary care to increase clinicians’ confidence in detecting dementia and lead to timely clinical evaluation, treatment, and referral to supportive resources.
CITATION:
Tabasa Ozawa ; Katherine J. Selzler ; Daniel E. Ball ; Amy Deckert ; Tim MacLeod ; Otelo Corrêa dos Santos Filho ; Ishtar Govia ; Janelle N. Robinson ; Hisatomo Kowa ; Mariana Lopez-Ortega ; Alison McKean ; Wendy Chambers ; Steven R. Smith ; Magda Baksh ; Deanna R. Willis ; Nicole R. Fowler ; Soeren Mattke ; The DAC Consortium (2025): Effects of the Davos Alzheimer's Collaborative early detection of cognitive impairment program on clinician attitudes, engagement, and confidence. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100038
MODIFIABLE RISK FACTORS FOR EARLY- AND LATE-ONSET DEMENTIA USING THE KOREAN NATIONAL HEALTH INSURANCE SERVICE DATABASE
Dougho Park, Myeonghwan Bang, Hyoung Seop Kim, Jong Hun Kim
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: Early-onset dementia (EOD) and late-onset dementia (LOD) may have distinct modifiable risk-factor profiles.
OBJECTIVE: To identify and compare factors associated with EOD and LOD using a nationwide cohort database.
DESIGN: Nationwide two nested case-control studies.
SETTING: We used the National Health Insurance Service-National Sample Cohort database (2004–2019).
PARTICIPANTS: The initial sample size was 514,866; 5157 EOD and 39,326 LOD cases were matched 1:1 with controls based on age, sex, and the Charlson Comorbidity Index.
MEASUREMENTS: Socioeconomic status, residential area, body mass index, alcohol consumption, smoking status, physical activity, blood pressure, and laboratory findings were analyzed. Multivariable logistic regression models were used to identify the risk factors.
RESULTS: Higher socioeconomic status and increased frequency of physical activity were associated with a lower risk of both EOD and LOD. Rural residence, heavy alcohol consumption, and higher fasting blood sugar levels were associated with an increased risk of LOD, although there was no significant association with EOD. Overall, these factors impacted LOD more strongly than EOD. Demographic and lifestyle factors had a greater effect on LOD than blood pressure and relevant laboratory findings.
CONCLUSION: Modifiable risk factors were associated with LOD and EOD. The influence of some modifiable risk factors was more pronounced in the LOD group than in the EOD group. Identifying modifiable risk factors associated with dementia can aid in the development of preventive strategies, underscoring the clinical importance of our findings.
CITATION:
Dougho Park ; Myeonghwan Bang ; Hyoung Seop Kim ; Jong Hun Kim (2025): Modifiable risk factors for early- and late-onset dementia using the Korean national health insurance service database. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100032
PROTOCOL FOR AN INTERGENERATIONAL RANDOMIZED CONTROLLED TRIAL TO ENHANCE PHYSICAL ACTIVITY IN OLDER ADULTS AT RISK FOR ALZHEIMER\'S DISEASE
Caitlin S. Walker, Adrián E. Noriega de la Colina, Linda Li, Carolynn Boulanger, Nagashree Thovinakere, Alix Noly-Gandon, Garance Barnoin, Mitchell Bennett, Jillian Caplan, Laurence Côté, Sarah Elbaz, Shania Fock Ka Bao, Ryan Kara, Nicolas Lavoie, Maggie Nguyen, Franciska Otaner, Helen Pallett-Wiesel, Johanie Victoria Piché, Andreanne Powers, Sofia Ricciardelli, Maiya R. Geddes
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: Physical inactivity is one of the most important modifiable risk factors for Alzheimer's disease in North America. Despite this, most older adults are physically inactive. It is currently unknown how to successfully motivate physical activity behavior in older adults at risk for Alzheimer's disease, and this knowledge is crucial for early and effective disease prevention. Prior research has shown that intergenerational social engagement and prosocial behaviours can enhance the health and well-being of older adults.
OBJECTIVES: This manuscript describes the design of a randomized controlled trial that will test the efficacy of a behavioral intervention to enhance physical activity in older adults at risk for Alzheimer's disease.
DESIGN/SETTING: This is a single-blinded, two-arm stratified randomized controlled trial that incorporates a hybrid efficacy and implementation design. Participants are randomized to an intervention or control condition in a 1:1 ratio and are stratified by a multimodal Alzheimer's disease risk score. All study visits are conducted remotely through videoconferencing.
PARTICIPANTS: The study aims to recruit 60 older adults with a first-degree family history of Alzheimer's disease from the PREVENT-AD cohort and 30 younger adults who are paired with older adults in the intervention condition.
INTERVENTION: Older participants in the intervention group will be paired with younger study partners and receive positive, daily messages over four weeks using a novel technology platform. The daily messages combine intergenerational social engagement (growing a virtual garden with a younger study partner) and prosocial goals (donations to charity after reaching step count goals).
MEASUREMENTS: The primary outcome is change in step count compared to baseline measured using a wrist-worn triaxial accelerometer. Secondary outcomes include time spent physically active, mood, generativity, loneliness, and cognition. Target mechanisms (social support and generativity) of physical activity engagement will be examined. Ease of use, acceptability, and feasibility of the technology as well as barriers and facilitators of participation will be assessed.
CONCLUSIONS: This research will advance our understanding of mechanisms and individual differences underlying successful physical activity engagement in older adults who are at risk for Alzheimer's disease. This knowledge will contribute to strategies for promoting health behaviours that can prevent the risk of Alzheimer's disease.
CITATION:
Caitlin S. Walker ; Adrián E. Noriega de la Colina ; Linda Li ; Carolynn Boulanger ; Nagashree Thovinakere ; Alix Noly-Gandon ; Garance Barnoin ; Mitchell Bennett ; Jillian Caplan ; Laurence Côté ; Sarah Elbaz ; Shania Fock Ka Bao ; Ryan Kara ; Nicolas Lavoie ; Maggie Nguyen ; Franciska Otaner ; Helen Pallett-Wiesel ; Johanie Victoria Piché ; Andreanne Powers ; Sofia Ricciardelli ; Maiya R. Geddes (2025): Protocol for an intergenerational randomized controlled trial to enhance physical activity in older adults at risk for Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100039
ASSOCIATIONS OF ISCHEMIC HEART DISEASE WITH BRAIN GLYMPHATIC MRI INDICES AND RISK OF ALZHEIMER\'S DISEASE
Ming-Liang Wang, Meng-Meng Yu, Zheng Sun, Jun-Jie Zhang, Jing-Kun Zhang, Xue Wu, Xiao-Er Wei, Yue-Hua Li, Alzheimer\'s Disease Neuroimaging Initiative
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: The impact of ischemic heart disease (IHD) on the brain glymphatic MRI indices and risk of Alzheimer's disease (AD) remains largely unclear. This study aimed to investigate the associations between IHD, brain glymphatic MRI indices and risk of AD.
METHODS: A total of 1385 non-dementia subjects (55.2 % male, mean age 73.53) were included. Diffusivity along the perivascular space (DTI-ALPS), free water (FW) and choroid plexus volume were used to reflect glymphatic function. The associations of IHD with MRI derived glymphatic indices, PET amyloid, tau and cognitive performance were explored by multiple regression analysis. IHD were tested as predictors of clinical progression using cox proportional hazards modeling. The mediation effect of MRI derived glymphatic indices on the relationship between IHD and cognitive changes was investigated.
RESULTS: Individuals with IHD exhibited glymphatic dysfunction revealed by lower DTI-ALPS (p = 0.035), higher FW (p < 0.001), and higher choroid plexus volume (p = 0.019). IHD had poorer cognitive performance in MMSE (p = 0.022), ADNI-MEM (p = 0.001) and ADNI-MF (p = 0.006), and more amyloid deposition (p = 0.007). IHD had a higher diagnostic conversion risk (HR = 1.321, 95 % CI = 1.003–1.741). IHD was associated with longitudinal cognitive decline in all cognitive tests (p < 0.05 for all) and FW (β = 0.012, 95 % CI 0.001, 0.023, p = 0.038). FW demonstrated an indirect effect (β = -0.0009, 95 % CI: -0.0034, -0.0001) and mediated 13.85 % effect for the relationship between IHD and ADNI-EF decline.
CONCLUSION: IHD is independently associated with AD risk, and brain glymphatic dysfunction may partially mediate this relationship.
CITATION:
Ming-Liang Wang ; Meng-Meng Yu ; Zheng Sun ; Jun-Jie Zhang ; Jing-Kun Zhang ; Xue Wu ; Xiao-Er Wei ; Yue-Hua Li ; Alzheimer's Disease Neuroimaging Initiative (2025): Associations of ischemic heart disease with brain glymphatic MRI indices and risk of Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100045
ASSOCIATIONS OF GLYCEMIC STATUS WITH DYNAMIC DISEASE TRAJECTORIES OF ATRIAL FIBRILLATION AND DEMENTIA
Chenglong Li, Daijun He, Yufan Liu, Chao Yang, Luxia Zhang, Rodica Pop-Busui
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: Atrial fibrillation (AF) has been associated with elevated dementia risk, while few studies have examined the role of the optimal glycemic status in disease trajectories of AF and dementia.
OBJECTIVES: We aim to evaluate associations between glycemic status with disease trajectories of AF and dementia, as well as major dementia subtypes, including Alzheimer's disease and vascular dementia.
DESIGN: Population-based cohort study.
SETTING: UK Biobank.
PARTICIPANTS: A total of 458 368 participants who were free of prevalent dementia and AF at baseline, with complete glycemic status assessment.
MEASUREMENTS: Based on clinical recommendations, we categorized glycemic status as low-normal (glycated hemoglobin [HbA1c] <5.5 %), normal (HbA1c 5.5 to 5.9 %), pre-diabetes (HbA1c 6.0 to 6.4 %), diabetes with HbA1c<7 %, and diabetes with HbA1c≥7 %. Outcomes including AF, dementia (all-cause and sub-type dementia), and death were ascertained via linkage to external registry databases. A multi-state survival analysis was conducted to evaluate disease trajectories of AF and dementia.
RESULTS: Better glycemic status was consistently associated with decreased hazards of trajectories of AF and dementia, including progression from AF to the comorbidity of AF and dementia. Among people with diabetes, those with HbA1c<7 % had a 31 % lower hazard (hazard ratio [HR], 0.69; 95 % confidence intervals [CI], 0.51–0.93) of progression from incident AF to dementia comorbidity, compared to those with HbA1c≥7 %. Similar risk reductions were found in individuals with pre-diabetes, normal HbA1c, and low-normal HbA1c, respectively. Strong dose-response associations were observed, with each 1 % increment in HbA1c related to a 28 % higher hazard of progression from AF to dementia comorbidity (HR,1.28; 95 % CI, 1.19–1.37). The glycemic status was most relevant for associations with disease trajectories of AF and vascular dementia, compared to trajectories of AF and Alzheimer's disease.
CONCLUSIONS: The better glycemic status was consistently associated with lower hazards of disease trajectories of AF and dementia, including the reduced risk of progression from incident AF to comorbidity of AF and dementia. These findings support the significance of reaching optimal glycemic status to alleviate the huge disease burden of both AF and dementia simultaneously.
CITATION:
Chenglong Li ; Daijun He ; Yufan Liu ; Chao Yang ; Luxia Zhang ; Rodica Pop-Busui (2025): Associations of glycemic status with dynamic disease trajectories of atrial fibrillation and dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100047
HEARING LOSS, DIET, AND COGNITIVE DECLINE: INTERCONNECTIONS FOR DEMENTIA PREVENTION
Xiaoran Liu, Uzma S. Akhtar, Todd Beck, Kyle Dennis, Denis A Evans, Kumar B Rajan
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: Hearing loss poses a significant global public health concern associated with cognitive decline. Among the many risk factors associated with Alzheimer's disease and related dementia (ADRD), hearing loss is the most prevalent sensory impairment in older adults and has emerged as a significant, yet often overlooked, modifiable risk factor for dementia.
OBJECTIVES: To access 1) the association between diet and risk of hearing loss in older adults and 2) the modifying effect of diet on the impact of hearing loss on cognitive decline in an aging population.
DESIGN: Prospective cohort study.
SETTING: The Chicago Health and Aging Project, a community-based cohort study
PARTICIPANTS: A total of 5,145 older adults (62 % non-Hispanic Black, 63 % female).
MEASUREMENTS: Self-reported hearing ability was assessed during each cycle of data collection. Diet was assessed by a 144-item Food Frequency Questionnaire. Diet quality was evaluated using a 144-item Food Frequency Questionnaire, focusing on adherence to dietary patterns such as Dietary Approaches to Stop Hypertension (DASH), Mediterranean, and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND). Cognitive function assessment was conducted during the in-home visits at each cycle. Four cognitive tests, including the East Boston tests of immediate and delayed recall, the mini-mental State Examination, and the Symbol Digit Modalities test, were included. We used linear mixed effect models to examine 1) the association of hearing loss and cognitive decline and 2) the association of diet on cognitive decline through modifying risk hearing loss. Discrete-time survival analysis examined the association between dietary patterns and the time to hearing impairment.
RESULTS: Among 5,145 participants included in the analyses, 747 (14.5 %) reported hearing loss, including 207 Black adults and 199 White adults. Each unit increase in the DASH, MedDiet, and MIND scores was associated with 19 % (95 % CI: 0.79, 0.94, P < 0.001), 11 % (95 % CI: 0.79, 1.00, P = 0.05), and 13 % (95 % CI: 0.87, 0.99, P < 0.05) lower risk for hearing loss, respectively. High adherence to the Western diet was associated with an earlier onset of hearing loss up to 14 months (P < 0.05). Participants had an increased rate of cognitive decline after reporting hearing loss. During follow-up, participants in the highest tertile of the DASH diet score who reported hearing loss experienced a 17 % faster cognitive decline (β = -0.07 ± 0.01) compared to those without hearing loss (β = -0.06 ± 0.003). However, this decline was significantly slower than that of participants observed in the lowest tertile of the DASH diet, who exhibited a 67 % faster cognitive decline (β = -0.10 ± 0.012, P = 0.05).
DISCUSSION: Healthy dietary patterns, particularly the DASH diet, was associated with a reduced risk of hearing loss and slower cognitive decline following hearing loss. Clinically, these findings underscore the importance of dietary quality in preserving cognitive health by potentially mitigating risk of hearing loss or delaying the onset of hearing loss in older adults.
CITATION:
Xiaoran Liu ; Uzma S. Akhtar ; Todd Beck ; Kyle Dennis ; Denis A Evans ; Kumar B Rajan (2025): Hearing loss, diet, and cognitive decline: interconnections for dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100052
PREVENTING DEMENTIA IN ITALY: ESTIMATIONS OF MODIFIABLE RISK FACTORS AND PUBLIC HEALTH IMPLICATIONS
Federica Asta, Guido Bellomo, Benedetta Contoli, Flavia L Lombardo, Valentina Minardi, Simone Salemme, Nicola Vanacore, Maria Masocco
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: Dementia is a major global public health challenge, with over 50 million cases in 2020, projected to reach 152 million by 2050. Effective prevention strategies are needed to reduce the impact of modifiable risk factors associated with dementia, particularly in countries with ageing populations like Italy. The Population Attributable Fraction (PAF) and Potential Impact Fraction (PIF) are key metrics for understanding and reducing dementia cases through targeted interventions.
OBJECTIVES: This study aimed to revise and expand PAF estimates for dementia in Italy, integrate them with PIF calculations, and assess the alignment of regional health policies with these risk factors. Additionally, the study explored regional variations in PAFs and evaluated the potential for reducing dementia incidence through feasible public health interventions.
DESIGN: A cross-sectional analysis was conducted using data from two national public health surveillance systems, PASSI and PASSI d'Argento (PdA), to estimate PAFs and PIFs for dementia at both national and regional levels. The study used data collected between 2017 and 2019.
SETTING: Data were drawn from 19 Italian regions and two autonomous provinces, providing national and subnational estimates of modifiable risk factors for dementia.
PARTICIPANTS: The study population included a nationally representative sample of 86,494 individuals aged 18–64 (PASSI) and 48,516 individuals aged 65 and older (PdA).
MEASUREMENTS: PAFs were calculated for 11 of the 12 modifiable risk factors identified by the Lancet Commission in 2021, with data from the PASSI and PdA systems. PIFs were calculated to estimate the potential reduction in dementia cases under different intervention scenarios. Regional variations in PAFs were assessed and aligned with health policies outlined in the Regional Prevention Plans.
RESULTS: The national combined PAF for 11 modifiable risk factors was 39.6 % (95 % CI: 20.8–55.9). Midlife hypertension and physical inactivity were the most significant contributors, accounting for 12.3 % of the total PAF. Cardiovascular risk factors collectively explained over 50 % of preventable dementia cases. Regional PAFs ranged from 31.7 % to 47.5 %, with a clear north-south gradient; southern regions exhibited higher PAFs due to cardiovascular factors. Despite broad consistency between national and regional PAFs, significant variability was found in how regions addressed risk factors, particularly air pollution. At the national level, a 10 % reduction in risk factors would prevent 54,495 dementia cases, with subnational PIFs ranging from 3.7 % to 6.0 %.
CONCLUSIONS: This study highlights the substantial potential for dementia prevention in Italy through targeted public health interventions. However, significant regional disparities in PAFs and the alignment of health policies underscore the need for a more nuanced, regionally tailored approach. Future strategies should integrate both PAF and PIF to maximize the impact of interventions, particularly in addressing cardiovascular risk factors. These findings can guide the development of evidence-based policies to reduce dementia incidence across Italy.
CITATION:
Federica Asta ; Guido Bellomo ; Benedetta Contoli ; Flavia L Lombardo ; Valentina Minardi ; Simone Salemme ; Nicola Vanacore ; Maria Masocco (2025): Preventing dementia in Italy: Estimations of modifiable risk factors and public health implications. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100055
PLASMA NEUROFILAMENT LIGHT MEDIATES THE EFFECTS OF APOLIPOPROTEIN E ON BRAIN ATROPHY AND COGNITIVE DECLINE IN THE COMORBID ALZHEIMER\'S DISEASE AND CEREBRAL SMALL VESSEL DISEASE
Chunhua Zhang, Bingyu Li, Kok Pin Ng, Yaojun Tai, Yuanming Tai, Xicheng Song, Min Kong, Maowen Ba, for Alzheimer\'s Disease Neuroimaging Initiative
J Prev Alz Dis 2025;3(12)
Show summaryHide summaryBACKGROUND: Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) often coexist in older adults and contribute to cognitive impairment. The Apolipoprotein E (APOE) ε4 allele and neuroaxonal injury, measured by plasma neurofilament light chain (NfL), are associated with an increased risk for both AD and CSVD. However, the relationship between APOE ε4, plasma NfL, and their association with the comorbidity of AD and CSVD remains unclear.
OBJECTIVE: To investigate the longitudinal relationship among APOE ε4, elevated plasma NfL, brain atrophy, and cognitive decline in individuals with comorbid AD and CSVD.
METHODS: We included 570 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, categorizing them into four groups based on amyloid-β positivity and CSVD burden. Linear mixed-effects models examined the association among APOE ε4, plasma NfL, brain volume measured by magnetic resonance imaging, and cognition over 2 years. Mediation analyses assessed the role of elevated plasma NfL in the relationship between APOE ε4, brain atrophy, and cognitive decline.
RESULTS: APOE ε4 carriers showed elevated plasma NfL levels, brain atrophy, and cognitive decline. Plasma NfL mediated the effects of APOE ε4 on brain atrophy and cognitive decline in participants with comorbid AD and CSVD.
CONCLUSION: Our findings suggest that neuroaxonal injury as a potential mechanism in the effects of APOE ε4 on brain atrophy and cognitive decline, highlighting the clinical utility of plasma NfL as a potential biomarker for disease progression and response to therapeutic intervention in comorbid AD and CSVD.
CITATION:
Chunhua Zhan ; Bingyu Li ; Kok Pin Ng ; Yaojun Tai ; Yuanming Tai ; Xicheng Song ; Min Kong ; Maowen Ba ; for Alzheimer's Disease Neuroimaging Initiative (2025): Plasma neurofilament light mediates the effects of Apolipoprotein E on brain atrophy and cognitive decline in the comorbid Alzheimer's disease and cerebral small vessel disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100054