02/2025 journal articles
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)
Show summaryHide summary
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