Ahead of print articles
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
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
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BACKGROUND: 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
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
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
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INTRODUCTION: 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
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
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
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BACKGROUND: 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
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
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
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Lecanemab 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
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
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BACKGROUND 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
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
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
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BACKGROUND: 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
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
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
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BACKGROUND: 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
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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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Most 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
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
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OBJECTIVES: 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
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°02 - 2025
IDENTIFYING PROTEOMIC PROGNOSTIC MARKERS FOR ALZHEIMER\'S DISEASE WITH SURVIVAL MACHINE LEARNING: THE FRAMINGHAM HEART STUDY
Yuanming Leng, Huitong Ding, Ting Fang Alvin Ang, Rhoda Au, P. Murali Doraiswamy, Chunyu Liu
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations.
METHODS: Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9 % women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in a separate group of 430 participants younger than 55 years (mean age 46, 56.7 % women).
RESULTS: Over a mean follow-up of 20 years, 132 (15.4 %) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4 + status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4 + status across 15–25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in the 339 participants (beta = −0.061, P = 0.046), 430 participants (beta = −0.060, P = 0.018), and the pooled 769 samples (beta = −0.058, P = 0.003).
CONCLUSION: These findings highlight the utility of machine learning method in identifying proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.
CITATION:
Yuanming Leng ; Huitong Ding ; Ting Fang Alvin Ang ; Rhoda Au ; P. Murali Doraiswamy ; Chunyu Liu (2025): Identifying proteomic prognostic markers for Alzheimer's disease with survival machine learning: The Framingham Heart Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100021
ASSOCIATION OF STATINS USE AND GENETIC SUSCEPTIBILITY WITH INCIDENCE OF ALZHEIMER\'S DISEASE
Zirong Ye, Jiahe Deng, Xiuxia Wu, Jingwen Cai, Sicheng Li, Xiaochun Chen, Jiawei Xin
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: The effect of statins use on the incidence of Alzheimer's disease (AD) is still under debate, and it could be modified by a series of factors.
OBJECTIVES: We aimed to examine the association of statins use with the risk of cognitive impairment and AD, and assess the moderating roles of genetic susceptibility and other individual-related factors.
DESIGN: A longitudinal study was conducted from the UK Biobank where individuals completed baseline surveys (2006–2010) and were followed (mean follow-up period: 9 years).
SETTING: A population-based study.
PARTICIPANTS: A total of 371,019 dementia-free participants (mean age 56.4 years; 53.6% female).
MEASUREMENTS: The effects of statins use on cognitive performance and incident AD were examined by using linear regression model and Cox proportional hazards regression model, respectively. We further evaluated the moderating roles of genetic risks and individual-related factors on both multiplicative and additive scales.
RESULTS: The findings showed statins use was associated with an increased risk of AD development [hazard ratio (HR) 1.19 (95% CI: 1.08, 1.30)] compared with no use of statins. We further found significant negative additive interactions of statins use with APOE ε4 allele. Besides, the effects of statins use would be modified by age, sex and cardiovascular diseases (CVDs).
DISCUSSIONS: A protective effect of statins use was observed in those who carried two APOE ε4 alleles. Also, sex, age and CVDs could modify the effects of statins use, which would provide insights for the guideline of the statins therapy.
CITATION:
Zirong Ye ; Jiahe Deng ; Xiuxia Wu ; Jingwen Cai ; Sicheng Li ; Xiaochun Chen ; Jiawei Xin (2025): Association of statins use and genetic susceptibility with incidence of Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100025
EFFICACY OF A GROUP-BASED 8-WEEK MULTICOMPONENT COGNITIVE TRAINING ON COGNITION, MOOD AND ACTIVITIES OF DAILY LIVING AMONG HEALTHY OLDER ADULTS: A TWO-YEAR FOLLOW-UP OF A RANDOMIZED CONTROLLED TRIAL
Patsri Srisuwan, Daochompu Nakawiro, Orawan Kuha, Supatcha Kengpanich, Kulachade Gesakomol, Sirinthorn Chansirikarnjana
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Cognitive training (CT) has been one of the important non-pharmaceutical interventions that could delay cognitive decline. Currently, no definite CT methods are available. Furthermore, little attention has been paid to the effect of CT on mood and instrumental activities of daily living (IADL).
OBJECTIVES: To assess the effectiveness of a multicomponent CT using a training program of executive functions, attention, memory and visuospatial functions (TEAM-V Program) on cognition, mood and instrumental ADL.
DESIGN: A randomized, single-blinded, treatment-as-usual controlled trial.
SETTING: Geriatric clinic in Bangkok, Thailand.
PARTICIPANTS: 80 nondemented community-dwelling older adults (mean age 65.7 ± 4.3 years).
INTERVENTION: The CT (TEAM-V) Program or the treatment-as-usual controlled group. The TEAM-V intervention was conducted over 5 sessions, with a 2-week interval between each session. A total of 80 participants were randomized (n = 40 the TEAM-V Program; n = 40 the control group).
MEASUREMENTS: The Thai version of Montreal Cognitive Assessment (MoCA), The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Thai version of Hospital Anxiety and Depression Scale (HADS) and The Chula ADL were used to assess at baseline, 6 months, 1 year and 2 years.
RESULTS: Compared with the control arm (n = 36), the TEAM-V Program (n = 39) was associated with significantly improved general cognition (MoCA, P = 0.02) at 2 years. Compared with baseline, participants receiving the TEAM-V Program were associated with significantly improved immediate recall (word recall task, P < 0.001), retrieval and retention of memory processes (word recognition task, P = 0.01) and attention (number cancellation part A, P = 0.01) at 2 years. No training effects on anxiety (P = 0.94), depression (P = 0.093) and IADL (P = 0.48) were detected.
CONCLUSIONS: The TEAM-V Program was effective in improving global cognitive function. Even though, the program did not significantly improve anxiety, depression and IADL compared with the control group, memory and attention improved in the intervention group compared with baseline. Further studies incorporating a larger sample size, longitudinal follow-up and higher-intensity CT should be conducted.
CITATION:
Patsri Srisuwan ; Daochompu Nakawiro ; Orawan Kuha ; Supatcha Kengpanich ; Kulachade Gesakomol ; Sirinthorn Chansirikarnjana (2025): Efficacy of a group-based 8-week multicomponent cognitive training on cognition, mood and activities of daily living among healthy older adults: A two-year follow-up of a randomized controlled trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100033
HIGH DEFINITION TRANSCRANIAL DIRECT CURRENT STIMULATION AS AN INTERVENTION FOR COGNITIVE DEFICITS IN ALZHEIMER\'S DEMENTIA: A RANDOMIZED CONTROLLED TRIAL
Christian LoBue, Hsueh-Sheng Chiang, Amber Salter, Shawn McClintock, Trung P. Nguyen, Rebecca Logan, Eric Smernoff, Seema Pandya, John Hart
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Recent disease-modifying treatments for Alzheimer's disease show promise to slow cognitive decline, but show no efficacy towards reducing symptoms already manifested.
OBJECTIVES: To investigate the efficacy of a novel noninvasive brain stimulation technique in modulating cognitive functioning in Alzheimer's dementia (AD).
DESIGN: Pilot, randomized, double-blind, parallel, sham-controlled study
SETTING: Clinical research site at UT Southwestern Medical Center
PARTICIPANTS: Twenty-five participants with clinical diagnoses of AD were enrolled from cognition specialty clinics.
INTERVENTION: Treatment consisted of high definition transcranial direct current stimulation (HD-tDCS) delivered for 20 min over the medial prefrontal cortex. Ten sessions of sham, 1 mA, or 2 mA stimulation were received.
MEASUREMENTS: Cognitive outcomes were measured at baseline, after the last HD-tDCS session, and 8-weeks post-treatment. The primary outcome was change in total learning and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) immediately post-treatment and at 8-weeks. Secondary outcomes included measures of language, processing speed, and executive functioning. A multi-stage approach was used to examine cognitive outcomes, which included evaluation of effect sizes, statistical effects, and rate of clinically meaningful responses.
RESULTS: In this pilot trial, no statistically significant differences on cognitive outcomes were found between sham and active HD-tDCS immediately post-treatment (p's > 0.05). However, moderate-to-large effect sizes were identified for enhanced RAVLT total learning (Cohen's d = 0.69–0.93) and phonemic fluency (d = 1.08–1.49) for both active HD-tDCS conditions compared to sham, with rates of clinically relevant improvement between 25 and 33%. Meaningful enhancement persisted to 8 weeks only for the 1 mA condition.
CONCLUSIONS
Multiple sessions of HD-tDCS over the medial prefrontal cortex appears to have potential to produce meaningful cognitive enhancements in a proportion of patients having AD with improvements maintained for at least 8 weeks in some.
CITATION:
Christian LoBue ; Hsueh-Sheng Chiang ; Amber Salter ; Shawn McClintock ; Trung P. Nguyen ; Rebecca Logan ; Eric Smernoff ; Seema Pandya ; John Hart (2025): High definition transcranial direct current stimulation as an intervention for cognitive deficits in Alzheimer's dementia: A randomized controlled trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100023
ULTRA-PROCESSED FOOD CONSUMPTION AND RISK OF DEMENTIA AND ALZHEIMER\'S DISEASE: THE FRAMINGHAM HEART STUDY
Galit Weinstein, Daniel Kojis, Ayantika Banerjee, Sudha Seshadri, Maura Walker, Alexa S. Beiser
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Ultra-processed food consumption is emerging as a risk factor for various cardiometabolic diseases, however its association with dementia and Alzheimer's disease has rarely been explored.
OBJECTIVES: We sought to examine whether ultra-processed food consumption is associated with risk of all-cause dementia and Alzheimer's disease among middle-age and older adults.
DESIGN: A prospective cohort study.
SETTING: The Framingham Heart Study, a single-site, community-based cohort study.
PARTICIPANTS: Offspring cohort participants who attended examination cycles 5 (1991-1995) and 7 (1998-2001) at age ≥60 years and who were dementia-free at baseline.
MEASUREMENTS: Nutritional information was retrieved from food frequency questionnaires, and ultra-processed food was categorized based on the NOVA system. Participants were followed-up for all-cause dementia and Alzheimer's disease. Cox regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) adjusting for potential confounders.
RESULTS: The study sample included 1,375 participants free of dementia and stroke at baseline (mean age 68 ± 6y, 54 % females). During a mean follow-up of 12.7 ± 6.0 years, 224 and 172 individuals were diagnosed with all-cause dementia and Alzheimer's disease, respectively. An interaction of ultra-processed food consumption with age was observed with regard to dementia and Alzheimer's disease (p for interaction = 0.02 and 0.007, respectively). Therefore, all analyses were stratified by the median age of 68 years. Among participants who were <68 years of age at baseline, each serving per day of ultra-processed food was associated with 13 % increased risk for Alzheimer's disease (HR = 1.13, 95 % CI:1.03-1.25), and consumption of ≥10 servings/day vs. <10 servings/day of ultra-processed food was associated with a 2.7-fold increase in Alzheimer's disease risk (HR = 2.71, 95 % CI:1.18-6.24), after adjustment for age, sex, education, total energy, metabolic factors and diet quality. The associations with all-cause dementia were less robust, and no significant findings were observed when age at baseline was 68 years or above.
CONCLUSIONS: Our findings suggest that consumption of ultra-processed food in middle-age may be linked with an increased risk for Alzheimer's disease. Future clinical studies are warranted to assess whether reduction of ultra-processed food consumption improves brain health.
CITATION:
Galit Weinstein ; Daniel Kojis ; Ayantika Banerjee ; Sudha Seshadri ; Maura Walker ; Alexa S. Beiser (2025): Ultra-processed food consumption and risk of dementia and Alzheimer's disease: The Framingham Heart Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100042
THE EFFECT OF SLEEP DISTURBANCES ON THE INCIDENCE OF DEMENTIA FOR VARYING LAG TIMES
Peter Alders, Almar Kok, Elisabeth M. van Zutphen, Jurgen A.H.R. Claassen, Dorly J.H. Deeg
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Few studies have addressed the association of sleep disturbances with incident dementia with long lag times. We add to this literature by investigating how lag times varying from 2.2 to 23.8 years affect the relationship between sleep disturbance and incident dementia in a Dutch cohort study on aging.
METHODS: Using eight waves of data from the Longitudinal Aging Study Amsterdam, we investigated the association of hours of sleep, difficulty falling asleep, interrupted sleep, and waking up early with incident dementia. For dementia an algorithm was used based on repeated measurements of cognitive tests and other data sources that provide strong indications of dementia. Sleep disturbances were assessed with a self-report questionnaire.
RESULTS: Of 2,218 participants, 237 (11%) developed dementia in the period 1992/3 to 2015/6. Participants ≥70 years more often reported sleep disturbances compared to those <70. Only for a short lag time (3 years), sleeping ≥9 h was associated with incident dementia. Sleeping ≤6 h, interrupted sleep and waking up early were associated with incident dementia, particularly for lag times ≥15 years.
DISCUSSION: We found that the association of sleep disturbances with incident dementia becomes stronger with longer lag times (particularly ≥15 years). Studies with lag times <15 years may suffer from reverse causation due to the changes in sleep patterns caused by the prodromal phase of neurodegenerative disease. The association of sleeping ≥9 h and the incidence of dementia in analyses with a short lag time seem to be the result of reverse causation.
CITATION:
Peter Alders ; Almar Kok ; Elisabeth M. van Zutphen ; Jurgen A.H.R. Claassen ; Dorly J.H. Deeg (2025): The effect of sleep disturbances on the incidence of dementia for varying lag times. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100024
CORE BLOOD BIOMARKERS OF ALZHEIMER\'S DISEASE: A SINGLE-CENTER REAL-WORLD PERFORMANCE STUDY
Federico Emanuele Pozzi, Elisa Conti, Giulia Remoli, Niccolò dell\'Orto, Simona Andreoni, Fulvio Da Re, Gessica Sala, Luca Cuffaro, Carlo Ferrarese, Ildebrando Appollonio, Chiara Paola Zoia, Lucio Tremolizzo
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: The new criteria for Alzheimer's disease pave the way for the introduction of core blood biomarkers of Alzheimer's disease (BBAD) into clinical practice. However, this depends on the demonstration of sufficient accuracy and robustness of BBADs in the intended population.
OBJECTIVES: To assess the diagnostic performance of core BBADs in our memory clinic, comparing them with cerebrospinal fluid (CSF) analysis.
DESIGN: Real-world cross-sectional observational study.
SETTING: Memory Clinic of Fondazione IRCCS “San Gerardo dei Tintori,” Monza, Italy.
PARTICIPANTS: n = 102 consecutive outpatients (mean age: 71.0 ± 7.6 years) with cognitive impairment undergoing routine lumbar puncture.
MEASUREMENTS: CSF Aβ40, Aβ42, tTau, and pTau181 levels were measured. Plasma biomarkers were evaluated using Lumipulse® G600II. Logistic regression and Receiver Operating Characteristic (ROC) analysis were used to assess biomarker performance. The diagnosis of Alzheimer's disease was based on CSF Aβ42/40 ratio.
RESULTS: Plasma pTau217 demonstrated the highest diagnostic accuracy (AUC=0.91), followed by pTau181 (AUC=0.88) and Aβ42/40 (AUC=0.83). In robustness analyses, only pTau217 and pTau181 performance remained consistent, while that of Aβ42/40 ratio declined with added random variability. pTau217 significantly outperformed other BBAD, with the exception of pTau181. pTau BBAD were significant predictors of baseline Mini-Mental State Examination scores.
CONCLUSIONS: Plasma pTau217, measured with Lumipulse®, is a robust and reliable BBAD for detecting amyloid pathology in a memory clinic setting, offering a practical and less invasive alternative to traditional CSF testing.
CITATION:
Federico Emanuele Pozzi ; Elisa Conti ; Giulia Remoli ; Niccolò dell'Orto ; Simona Andreoni ; Fulvio Da Re ; Gessica Sala ; Luca Cuffaro ; Carlo Ferrarese ; Ildebrando Appollonio ; Chiara Paola Zoia ; Lucio Tremolizzo (2025): Core blood biomarkers of Alzheimer's disease: A single-center real-world performance study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100027
LIFESTYLE INTERVENTIONS FOR DEMENTIA RISK REDUCTION: A REVIEW ON THE ROLE OF PHYSICAL ACTIVITY AND DIET IN WESTERN AND ASIAN COUNTRIES
Amelia Nur Vidyanti, Fitri Rahmawati, Rifki Habibi Rahman, Astuti Prodjohardjono, Abdul Gofir
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryDementia, is a critical global public health challenge with no effective pharmacological treatments. Recent research highlights the significant role of lifestyle interventions, particularly physical activity and dietary habits, in mitigating cognitive decline among the elderly and preventing the progression to dementia in individuals with Mild Cognitive Impairment (MCI). This comprehensive review explores the impact of physical exercise and dietary approaches on cognitive health, comparing strategies adopted in Western and Asian countries. Physical activity, including aerobic, resistance, balance training, and dual-task exercises, has been shown to enhance neurogenesis, improve cerebral blood flow, and delay cognitive decline. In Western countries, structured regimens such as the Mediterranean (MedDiet) and MIND diets are prominent, while Asian countries often integrate traditional mind-body practices like Tai Chi and culturally relevant diets rich in antioxidants and polyphenols. Although both regions recognize the importance of lifestyle changes in reducing dementia risk, their approaches differ significantly, shaped by cultural norms and dietary preferences. This review underscores the need for culturally tailored public health strategies to promote cognitive health globally, highlighting the importance of individualized approaches in MCI and dementia prevention.
CITATION:
Amelia Nur Vidyanti ; Fitri Rahmawati ; Rifki Habibi Rahman ; Astuti Prodjohardjono ; Abdul Gofir (2025): Lifestyle interventions for dementia risk reduction: A review on the role of physical activity and diet in Western and Asian Countries. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100028
BLOOD-BRAIN BARRIER INTEGRITY DISRUPTION IS ASSOCIATED WITH BOTH CHRONIC VASCULAR RISK FACTORS AND WHITE MATTER HYPERINTENSITIES
James Xiao Yuan Chen, Ashwati Vipin, Gurveen Kaur Sandhu, Yi Jin Leow, Fatin Zahra Zailan, Pricilia Tanoto, Ee Soo Lee, Khang Leng Lee, Christine Cheung, Nagaendran Kandiah
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Cardiovascular risk factors (CRFs) like hypertension, high cholesterol, and diabetes mellitus are increasingly linked to cognitive decline and dementia, especially in cerebral small vessel disease (cSVD). White matter hyperintensities (WMH) are closely associated with cognitive impairment, but the mechanisms behind their development remain unclear. Blood-brain barrier (BBB) dysfunction may be a key factor, particularly in cSVD.
OBJECTIVE: This study explores the relationship between CRFs, BBB integrity, and WMH burden.
DESIGN, SETTING, AND PARTICIPANTS: The study included 155 participants from the Biomarkers and Cognition Study, Singapore (BIOCIS). CRFs were assessed through blood tests for glucose and lipid profiles, and blood pressure measurements. WMH volumes were quantified using MRI.
MEASUREMENTS: BBB integrity was evaluated using a Transendothelial Electrical Resistance (TEER) assay with human brain microvascular endothelial cells (hBMEC) exposed to participant plasma.
RESULTS: Plasma from individuals with a higher WMH burden was associated with increased BBB disruption in hBMEC. Higher systolic and diastolic blood pressure, as well as body mass index, were correlated with greater BBB disruption. Regression analyses revealed that elevated blood glucose and lipid levels were linked to increased BBB disruption. Both periventricular and subcortical WMH burdens were associated with increased BBB disruption.
CONCLUSION: This study highlights a relationship between CRFs, BBB disruption, and WMH burden, suggesting that CRFs may impair BBB integrity and contribute to WMH and cognitive decline in cSVD.
CITATION:
James Xiao Yuan Chen ; Ashwati Vipin ; Gurveen Kaur Sandhu ; Yi Jin Leow ; Fatin Zahra Zailan ; Pricilia Tanoto ; Ee Soo Lee ; Khang Leng Lee ; Christine Cheung ; Nagaendran Kandiah (2025): Blood-brain barrier integrity disruption is associated with both chronic vascular risk factors and white matter hyperintensities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100029
BASAL FOREBRAIN GLOBAL FUNCTIONAL CONNECTIVITY IS PRESERVED IN ASYMPTOMATIC PRESENILIN-1 E280A MUTATION CARRIERS: RESULTS FROM THE COLOMBIA COHORT
Alice Grazia, Martin Dyrba, Nunzio Pomara, Anna G. Temp, Michel J. Grothe, Stefan J. Teipel, Alzheimer\'s Prevention Initiative (API) Autosomal-Dominant Alzheimer\'s Disease (ADAD) Trial
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Imaging studies showed early atrophy of the cholinergic basal forebrain in prodromal sporadic Alzheimer's disease and reduced posterior basal forebrain functional connectivity in amyloid positive individuals with subjective cognitive decline. Similar investigations in familial cases of Alzheimer's disease are still lacking.
OBJECTIVES: To test whether presenilin-1 E280A mutation carriers have reduced basal forebrain functional connectivity and whether this is linked to amyloid pathology.
DESIGN: This is a cross-sectional study that analyzes baseline functional imaging data.
SETTING: We obtained data from the Colombia cohort Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial.
PARTICIPANTS: We analyzed data from 215 asymptomatic subjects carrying the presenilin-1 E280A mutation [64% female; 147 carriers (M = 35 years), 68 noncarriers (M = 40 years)].
MEASUREMENTS: We extracted functional magnetic resonance imaging data using seed-based connectivity analysis to examine the anterior and posterior subdivisions of the basal forebrain. Subsequently, we performed a Bayesian Analysis of Covariance to assess the impact of carrier status on functional connectivity in relation to amyloid positivity. For comparison, we also investigated hippocampus connectivity.
RESULTS: We found no effect of carrier status on anterior (Bayesian Factor10 = 1.167) and posterior basal forebrain connectivity (Bayesian Factor10 = 0.033). In carriers, we found no association of amyloid positivity with basal forebrain connectivity.
CONCLUSIONS: We falsified the hypothesis of basal forebrain connectivity reduction in preclinical mutation carriers with amyloid pathology. If replicated, these findings may not only confirm a discrepancy between familial and sporadic Alzheimer's disease, but also suggest new potential targets for future treatments.
CITATION:
Alice Grazia ; Martin Dyrba ; Nunzio Pomara ; Anna G. Temp ; Michel J. Grothe ; Stefan J. Teipel ; Alzheimer's Prevention Initiative (API) Autosomal-Dominant Alzheimer's Disease (ADAD) Trial (2025): Basal forebrain global functional connectivity is preserved in asymptomatic presenilin-1 E280A mutation carriers: Results from the Colombia cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100030
CEREBRAL PERFUSION CORRELATES WITH AMYLOID DEPOSITION IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER\'S DISEASE
Caixia Wang, Deli Ji, Xiao Su, Fang Liu, Yanxin Zhang, Qingzheng Lu, Li Cai, Ying Wang, Wen Qin, Gebeili Xing, Peng Liu, Xin Liu, Meili Liu, Nan Zhang
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Changes in cerebral blood flow (CBF) may contribute to the initial stages of the pathophysiological process in patients with Alzheimer's disease (AD). Hypoperfusion has been observed in several brain regions in patients with mild cognitive impairment (MCI). However, the clinical significance of CBF changes in the early stages of AD is currently unclear.
OBJECTIVES: The aim of this study was to investigate the characteristics, diagnostic value and cognitive correlation of cerebral perfusion measured with arterial spin labeling (ASL) magnetic resonance imaging (MRI) in patients with MCI due to AD.
DESIGN, SETTING AND PARTICIPANTS: A total of fifty-nine MCI patients and 49 cognitively unimpaired controls (CUCs) were recruited and underwent multimodal MRI scans, including pseudocontinuous ASL, and neurocognitive testing. MCI patients were dichotomously classified according to the presence of amyloid deposition on 11C-labelled Pittsburgh compound B (PiB) positron emission tomography (PET).
MEASUREMENTS: The differences in CBF and expression of the AD-related perfusion pattern (ADRP), established by spatial covariance analysis in our previous study, were compared between the PiB+ MCI group and the CUC group and between the PiB+ and PiB- MCI groups. The diagnostic accuracy and correlations with cognitive function scores for CBF and ADRP expression were further analyzed.
RESULTS:
Hypoperfusion in the precuneus and posterior cingulate cortex (PCC) was more characteristic of patients with MCI due to AD than of those with non-AD-related MCI. The relative regional CBF value of the left precuneus best distinguished patients with MCI due to AD from CUCs and patients with MCI due to non-AD conditions. Cerebral perfusion, as indicated by either the relative regional CBF or the expression score of the ADRP, was strongly correlated with certain cognitive function scores.
CONCLUSIONS: Here, we show that changes in CBF in the precuneus/PCC are promising MRI biomarkers for the identification of an AD etiology in patients with MCI. ASL, a noninvasive and cost-effective tool, has broad application prospects in the screening and early diagnosis of AD.
CITATION:
Caixia Wang ; Deli Ji ; Xiao Su ; Fang Liu ; Yanxin Zhang ; Qingzheng Lu ; Li Cai ; Ying Wang ; Wen Qin ; Gebeili Xing ; Peng Liu ; Xin Liu ; Meili Liu ; Nan Zhang (2025): Cerebral perfusion correlates with amyloid deposition in patients with mild cognitive impairment due to Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100031
ENHANCING DEMENTIA PREDICTION: A 19-YEAR VALIDATION OF THE CAIDE RISK SCORE WITH INSULIN RESISTANCE AND APOE Ε4 INTEGRATION IN A POPULATION-BASED COHORT
Elina Pietilä, Eliisa Löyttyniemi, Seppo Koskinen, Jenni Lehtisalo, Matti Viitanen, Juha O. Rinne, Antti Jula, Laura L. Ekblad
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Dementia is a significant cause of disability and dependency. Persons with high dementia risk but intact cognition will benefit from preventive interventions.
OBJECTIVES: The aim was to validate dementia risk score Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) in a national population-based cohort with data on age, education, hypertension, obesity, hyperlipidemia and physical activity. Secondly, we examined if substituting obesity item with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) would improve predictive value of CAIDE risk score.
DESIGN: Longitudinal, population-based cohort study.
SETTING: General population, Finland.
PARTICIPANTS: Representative sample of Finnish adult population aged over 30 years from Health 2000 Survey (n = 5,806).
MEASUREMENTS: CAIDE dementia risk score and substituting BMI with HOMA-IR.
RESULTS: Dementia was diagnosed in 571 (9.8 %) participants during the 19 years follow-up. CAIDE risk score predicted dementia well: AUC (area under curve) ROC (receiver-operating characteristic) was 0.78 (95 % CI from 0.76 to 0.79). Secondly, replacing obesity with HOMA-IR in CAIDE risk score generated similar results: ROC AUC 0.78 (95 % CI from 0.76 to 0.80). Adding APOE ε4 status further improved predictive value of risk score: ROC AUC 0.81 (95 % CI from 0.80 to 0.83).
CONCLUSIONS: CAIDE dementia risk score predicts dementia well in a national population-based cohort. Adding APOE ε4 genotype improved predictive value of risk score. Insulin resistance measured by HOMA-IR is comparable to obesity as part of CAIDE risk score. These findings imply that CAIDE risk score is applicable for assessing risk of dementia and highlight importance of modifiable risk factors of dementia.
CITATION:
Elina Pietilä ; Eliisa Löyttyniemi ; Seppo Koskinen ; Jenni Lehtisalo ; Matti Viitanen ; Juha O. Rinne ; Antti Jula ; Laura L. Ekblad (2025): Enhancing dementia prediction: A 19-year validation of the CAIDE risk score with insulin resistance and APOE ε4 integration in a population-based cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100034
DETERMINANTS OF DEMENTIA DIAGNOSIS IN U.S. PRIMARY CARE IN THE PAST DECADE: A SCOPING REVIEW
Chelsea G. Cox, Barbara L. Brush, Lindsay C. Kobayashi, J. Scott Roberts
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Alzheimer's disease and related dementias (ADRD) are chronically underdiagnosed in the U.S., particularly among minoritized racial and ethnic groups. Primary care providers are at the forefront of diagnosis given the increasing prevalence of cases and shortage of dementia specialists. Advances in policy, detection, and treatment in the past decade necessitate an updated review of the current state of determinants of ADRD diagnosis in U.S. primary care settings.
METHODS: Following Joanna Briggs Institute guidelines, we conducted a scoping literature review on ADRD diagnosis among older adults in U.S. primary care settings. Studies published in English from January 2010 to January 2024 were retrieved from PubMed, PsycINFO, and CINAHL. We extracted primary data on study characteristics and synthesized key findings according to facilitators, barriers, and rates of diagnosis in primary care.
RESULTS: Of 563 articles retrieved, 12 met eligibility criteria. Three studies reported rates of diagnosis, and all but one reported facilitators and/or barriers to diagnosis. ADRD remains underdiagnosed in primary care settings, especially in the earliest symptomatic stage (i.e., mild cognitive impairment). Multi-level barriers and facilitators were identified including individual beliefs about ADRD (e.g., value of early diagnosis), interpersonal relationships between patients and their family members and providers (e.g., importance of an established clinical relationship), and healthcare system limitations (e.g., insufficient resources and training).
CONCLUSION: Despite national policy efforts to improve timely diagnosis of ADRD, underdiagnosis remains a clinical and public health challenge. Increased attention to social and community contexts will be important for future research and intervention.
CITATION:
Chelsea G. Cox ; Barbara L. Brush ; Lindsay C. Kobayashi ; J. Scott Roberts (2025): Determinants of dementia diagnosis in U.S. primary care in the past decade: A scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100035
MICROSTRUCTURAL WHITE MATTER INJURY CONTRIBUTES TO COGNITIVE DECLINE: BESIDES AMYLOID AND TAU
He-Ying Hu, Hong-Qi Li, Wei-Kang Gong, Shu-Yi Huang, Yan Fu, Hao Hu, Qiang Dong, Wei Cheng, Lan Tan, Lan Tan, Jin-Tai Yu
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: Cognitive decline and the progression to Alzheimer's disease (AD) are traditionally associated with amyloid-beta (Aβ) and tau pathologies. This study aims to evaluate the relationships between microstructural white matter injury, cognitive decline and AD core biomarkers.
METHODS: We conducted a longitudinal study of 566 participants using peak width of skeletonized mean diffusivity (PSMD) to quantify microstructural white matter injury. The associations of PSMD with changes in cognitive functions, AD pathologies (Aβ, tau, and neurodegeneration), and volumes of AD-signature regions of interest (ROI) or hippocampus were estimated. The associations between PSMD and the incidences of clinical progression were also tested. Covariates included age, sex, education, apolipoprotein E4 status, smoking, and hypertension.
RESULTS: Higher PSMD was associated with greater cognitive decline (β=-0.012, P < 0.001 for Mini-Mental State Examination score; β<0, P < 0.05 for four cognitive domains) and a higher risk of clinical progression from normal cognition to mild cognitive impairment (MCI) or AD (Hazard ratio=2.11 [1.38–3.23], P < 0.001). These associations persisted independently of amyloid status. PSMD did not predict changes in Aβ or tau levels, but predicted changes in volumes of AD-signature ROI (β=-0.003, P < 0.001) or hippocampus (β=-0.002, P = 0.010). Besides, the whole-brain PSMD could predict cognitive decline better than regional PSMDs.
CONCLUSIONS: PSMD may be a valuable biomarker for predicting cognitive decline and clinical progression to MCI and AD, providing insights besides traditional Aβ and tau pathways. Further research could elucidate its role in clinical assessments and therapeutic strategies.
CITATION:
He-Ying Hu ; Hong-Qi Li ; Wei-Kang Gong ; Shu-Yi Huang ; Yan Fu ; Hao Hu ; Qiang Dong ; Wei Cheng ; Lan Tan ; Mei Cui ; Jin-Tai Yu (2025): Microstructural white matter injury contributes to cognitive decline: Besides amyloid and tau. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2024.100037
DISTINCT CSF Α-SYNUCLEIN AGGREGATION PROFILES ASSOCIATED WITH ALZHEIMER\'S DISEASE PHENOTYPES AND MCI-TO-AD CONVERSION
Yanfei Ding, Lingbing Wang, Jun Liu, Yulei Deng, Yang Jiao, Aonan Zhao, Alzheimer\'s Disease Neuroimaging Initiative (ADNI)
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: α-Synuclein (α-Syn) pathology is present in 30–50 % of Alzheimer's disease (AD) patients, and its interactions with tau proteins may further exacerbate pathological changes in AD. However, the specific role of different aggregation forms of α-Syn in the progression of AD remains unclear.
OBJECTIVES: To explore the relationship between various aggregation types of CSF α-Syn and Alzheimer's disease progression.
DESIGN: We conducted a retrospective analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine the association between different α-Syn aggregation forms—Syn0 (no detectable α-Syn aggregates) and Syn1 (α-Syn aggregates detected, resembling those found in Parkinson's disease)—with the pathological and clinical features of AD. Additionally, we evaluated their potential as predictors of conversion from mild cognitive impairment (MCI) to AD.
SETTING: The ADNI database.
PARTICIPANTS: A total of 250 participants, including 70 cognitively normal controls, 119 patients diagnosed with MCI, and 61 patients diagnosed with AD.
MEASUREMENTS: Pearson correlation was employed to assess the relationship between α-Syn levels and cerebrospinal fluid (CSF) biomarkers, including total tau (T-tau), phosphorylated tau (p-tau), and amyloid-β42 (Aβ42). Multivariate Cox proportional hazards models were applied, adjusting for APOE4 status, age, and sex, to determine the association between α-Syn forms and AD-related pathological and clinical outcomes. Kaplan-Meier curves were used to evaluate the prognostic value of different α-Syn aggregation states in predicting the conversion from MCI to AD.
RESULTS: Compared with controls, overall MCI and AD patients had elevated α-Syn levels. Notably, in the α-Syn0 group, α-Syn levels were increased in the MCI patients and further increased in AD patients, whereas in the α-Syn1 group, α-Syn levels did not significantly differ across diagnostic groups. Both in the α-Syn0 and α-Syn1 groups, α-Syn levels were found to correlate more strongly with CSF tau levels than with Aβ42, indicating a possible role for α-Syn in tau-related pathology in AD. Importantly, α-Syn0-AD patients exhibited more rapid cognitive decline and greater hippocampal atrophy than α-Syn1-AD patients. However, MCI patients with CSF α-Syn1 aggregation status had an increased risk of conversion to AD.
CONCLUSIONS: CSF α-Syn is associated with tau pathology and neurodegeneration in Alzheimer's disease. The distinct aggregation profiles of α-Syn serve as valuable biomarkers, offering insights into differing prognoses in AD and aiding in the prediction of early disease progression.
CITATION:
Yanfei Ding ; Lingbing Wang ; Jun Liu ; Yulei Deng ; Yang Jiao ; Aonan Zhao ; Alzheimer's Disease Neuroimaging Initiative (ADNI) (2025): Distinct CSF α-synuclein aggregation profiles associated with Alzheimer's disease phenotypes and MCI-to-AD conversion. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100040
ASSOCIATIONS OF EARLY-ONSET CORONARY HEART DISEASE AND GENETIC SUSCEPTIBILITY WITH INCIDENT DEMENTIA AND WHITE MATTER HYPERINTENSITY: A PROSPECTIVE COHORT STUDY
Jie Liang, Yanyu Zhang, Wenya Zhang, Yang Pan, Darui Gao, Jingya Ma, Yuling Liu, Yiwen Dai, Mengmeng Ji, Wuxiang Xie, Fanfan Zheng
J Prev Alz Dis 2025;2(12)
Show summaryHide summaryBACKGROUND: The associations of early-onset coronary heart disease (CHD) and genetic susceptibility with incident dementia and brain white matter hyperintensity (WMH) remain unclear. Elucidation of this problem could promote understanding of the neurocognitive impact of early-onset CHD and provide suggestions for the prevention of dementia.
OBJECTIVES: This study aimed to investigate whether observed and genetically predicted early-onset CHD were related to subsequent dementia and WMH volume.
DESIGN: Prospective cohort study.
SETTING: UK Biobank.
PARTICIPANTS: 500 671 individuals without dementia at baseline.
MEASUREMENTS: Early-onset CHD (male ≤55 years; female ≤65 years) was ascertained using hospital inpatient records. Incident dementia including all-cause dementia, Alzheimer's disease, and vascular dementia was ascertained using hospital inpatient records, mortality register data, and self-reported data. WMH volume was measured through brain magnetic resonance imaging (MRI). Cox proportional hazards models and linear regression models were used to analyze the associations of early-onset CHD with incident dementia and WMH. Subsequently, a polygenetic risk score (PRS) analysis was conducted to investigate the associations of genetically predicted early-onset CHD with outcomes.
RESULTS: Among 500 671 individuals (female: 272 669, 54.5%; mean age: 57.0 ± 8.1 years), 9 294 dementia occurred during a median follow-up of 13.8 years. Compared with the non-CHD group, both early-onset (n = 16 133) and late-onset CHD (n = 43 944) groups had higher risks of developing dementia (hazard ratio [HR]: 1.99, 95% confidence interval [CI]: 1.81 to 2.19 for early-onset group; HR: 1.20, 95% CI: 1.14 to 1.27 for late-onset group). Among CHD participants, early-onset CHD was associated with a significantly higher risk of incident dementia, compared with late-onset CHD (HR: 1.56, 95% CI: 1.39 to 1.75). In a subset of 40 290 individuals who completed brain MRI scans during a median follow-up of 9.3 years, participants with early-onset CHD exhibited the largest WMH volume among the three groups (early-onset CHD, late-onset CHD, and non-CHD, Ptrend<0.001). The PRS analysis supported the associations of early-onset CHD with dementia (odds ratio [OR] for the highest quartile: 1.37, 95% CI: 1.28 to 1.46, Ptrend<0.001) and WMH volume (β for the highest quartile: 0.042, 95% CI: 0.017 to 0.068, Ptrend=0.002).
CONCLUSIONS: Early-onset CHD and genetic susceptibility are associated with a higher risk of incident dementia and a larger WMH volume. Additional attention should be paid to the neurocognitive status of individuals with early-onset CHD.
CITATION:
Jie Liang ; Yanyu Zhang ; Wenya Zhang ; Yang Pan ; Darui Gao ; Jingya Ma ; Yuling Liu ; Yiwen Dai ; Mengmeng Ji ; Wuxiang Xie ; Fanfan Zheng (2025): Associations of early-onset coronary heart disease and genetic susceptibility with incident dementia and white matter hyperintensity: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100041
CORRIGENDUM TO “MULTIOMICS BLOOD-BASED BIOMARKERS PREDICT ALZHEIMER\'S PREDEMENTIA WITH HIGH SPECIFICITY IN A MULTICENTRIC COHORT STUDY” [THE JOURNAL OF PREVENTION OF ALZHEIMER\'S DISEASE 2024;11(3):567–581]
B. Souchet, B. Souchet, M. Heuillet, A. Dupuy-Gayral, E. Haudebourg, C. Pech, A. Berthemy, F. Autelitano, B. Billoir, K. Domoto-Reilly, C. Fowler, T. Rabowski, S. Jayadev, C.L. Masters, J. Braudeau
J Prev Alz Dis 2025;2(12)
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CITATION:
B. Souchet ; A. Michaïl ; M. Heuillet ; A. Dupuy-Gayral ; E. Haudebourg ; C. Pech ; A. Berthemy ; F. Autelitano ; B. Billoir ; K. Domoto-Reilly ; C. Fowler ; T. Rabowski ; S. Jayadev ; C.L. Masters ; J. Braudeau (2025): Corrigendum to “Multiomics Blood-Based Biomarkers Predict Alzheimer's Predementia with High Specificity in a Multicentric Cohort Study” [The Journal of Prevention of Alzheimer's Disease 2024;11(3):567–581]. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2024.100026