Ahead of print articles
EDITORIAL: TREATMENTS FOR ALZHEIMER’S AND THE DECLARATION OF HELSINKI
Timothy Daly, Andi Olluri, Markku Kurkinen
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Timothy Daly ; Andi Olluri ; Markku Kurkinen (2025): Editorial: Treatments for Alzheimer’s and the declaration of Helsinki. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100260
EARLY DETECTION OF ALZHEIMER’S DISEASE USING SMALL RNAS. RESULTS FROM THE EPAD COHORT
Tobias Sikosek, Marco Heuvelman, Jagoda Mika, Mustafa Kahraman, Julia Jehn, Maurice Frank, Alberto Daniel-Moreno, Jessika Ceiler, Jasmin Skottke, Marta Sanchez-Delgado, Patrick Neubert, Christina Rudolf, Kaja Tikk, Rastislav Horos, Jeffrey L. Cummings, Josie Butchart, Craig Ritchie, Jean Manson, Bruno R. Steinkraus, the EPAD consortium
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BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and early diagnosis is crucial to enable effective interventions. Currently, Alzheimer's disease is diagnosed through cognitive assessments, brain imaging and fluid biomarkers focused on determining amyloid (A) and, tau (T) protein levels as well as neurodegeneration (N) in the AT(N) framework. Prognostic biomarkers for predicting cognitive decline within the amyloid positive (Aβ+) individuals would further strengthen the framework.
OBJECTIVES: This study evaluated small RNAs as novel auxiliary biomarkers, independent of the AT(N) framework, either alone or in combination with established protein markers, for detecting the earliest cognitive decline in AD.
DESIGN: The European Prevention of Alzheimer’s Disease (EPAD) clinical trial platform is a prospective, multi-center study designed to investigate biomarkers for preclinical and prodromal AD.
SETTING: Peripheral whole blood RNA sequencing was performed on participants across Europe with no cognitive impairment or very mild cognitive impairment (MCI), stratified by cerebrospinal fluid amyloid levels.
PARTICIPANTS: 1,913 participants, 50 years or older and free of dementia diagnosis at enrollment, were analyzed.
INTERVENTION: (if any) Not applicable.
MEASUREMENTS: Ultra-deep small RNA sequencing was performed on whole blood samples using a refined blocking protocol to eliminate highly abundant erythroid small RNAs, and thereby to open sequencing bandwidth for the discovery of less abundant biomarker RNAs. Biomarker RNAs were deconvolved into plasma or blood cell origin and analyzed for functional relevance. We define high and low amyloid groups based on a cutoff on the p-tau181/Aβ1-42 ratio as determined from cerebrospinal fluid.
RESULTS: We identified a combination of small RNAs that predicted early cognitive decline (Clinical Dementia Rating of 0.5) with an area under the receiver-operator curve of ∼0.7. Notably, when focusing on individuals with cognitive decline and high amyloid burden (Aβ+), the predictive accuracy improved to an AUC of 0.77. This performance could be extended to the entire cohort when combining blood RNA and CSF amyloid markers (AUC 0.76). We conducted bioinformatic analyses to interrogate the likely functional relevance of these small RNAs, uncovering several links to dementia-relevant pathways, including neuronal, cardiovascular, and inflammatory activities. Our findings also suggest that small nucleolar RNAs warrant further investigation as potential disease-relevant markers, in addition to microRNAs.
CONCLUSIONS: Integrating small RNA biomarkers with protein-based assays offers preliminary evidence for stratifying MCI, particularly within the amyloid positive continuum. Small nucleolar RNAs and microRNAs warrant further exploration as complementary diagnostic tools, and their use may enable more precise and effective interventions.
CITATION:
Tobias Sikosek ; Marco Heuvelman ; Jagoda Mika ; Mustafa Kahraman ; Julia Jehn ; Maurice Frank ; Alberto Daniel-Moreno ; Jessika Ceiler ; Jasmin Skottke ; Marta Sanchez-Delgado ; Patrick Neubert ; Christina Rudolf ; Kaja Tikk ; Rastislav Horos ; Jeffrey L. Cummings ; Josie Butchart ; Craig Ritchie ; Jean Manson ; Bruno R. Steinkraus ; the EPAD consortium (2025): Early detection of Alzheimer’s disease using small RNAs. Results from the EPAD cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100257
EDITORIAL : STRUCTURAL EQUATION MODELING CONFIRMS INTERACTION OF ALZHEIMER’S DISEASE AND VASCULAR DISEASE IN HIPPOCAMPAL INJURY
Gary A. Rosenberg
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CITATION:
Gary A. Rosenberg (2025): Editorial: Structural equation modeling confirms interaction of Alzheimer’s disease and vascular disease in hippocampal injury. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100255
TARGETING COGNITIVE AGING WITH CURCUMIN SUPPLEMENTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS
Lirong Yu, Na Li, Bin Li, Kaisy Xinhong Ye, Jiuyu Guo, Jiatong Shan, Luwen Cao, Mei Song, Yanyu Wang, Tih-Shih Lee, Andrea B Maier, Lei Feng
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BACKGROUND: Cognitive aging is a growing public health concern, and curcumin, a bioactive compound derived from turmeric, has been proposed as a potential intervention to support cognitive function due to its anti-inflammatory and antioxidant properties.
OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the effects of curcumin on cognitive outcomes related to aging.
METHODS: A comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus was conducted to identify studies published up to June 18, 2024, including both in vivo preclinical animal studies and randomized controlled trials (RCTs) assessing curcumin's effects on cognitive function. In vivo animal studies using Alzheimer’s disease (AD) models and RCTs in human participants were included. Data were extracted and analyzed using meta-analytic techniques.
RESULTS: In preclinical in vivo murine studies (n = 25; total animals = 572), curcumin consistently improved both acquisition memory (SMD = -1.78, 95 % CI: -2.12 to -1.43) and retention memory (SMD = 2.36, 95 % CI: 1.72 to 3.00) in rodent models of AD. Ten human studies include 531 participants. Overall, curcumin showed no significant effect on global cognitive outcomes compared to placebo (SMD = 0.14, 95 % CI: -0.78 to 1.07). Subgroup analyses revealed significant improvements in working memory (SMD = 1.01, 95 % CI: 0.15 to 1.87) and processing speed (SMD = 0.37, 95 % CI: 0.07 to 0.67). The incidence of adverse events was higher in the curcumin group than in the control group.
CONCLUSIONS: Preclinical in vivo evidence suggests curcumin enhances cognitive function in AD models. However, human studies show inconsistent findings with benefits limited to specific cognitive domains. Larger, well-designed randomized controlled trials are needed to establish curcumin's efficacy and safety in cognitive aging.
CITATION:
Lirong Yu ; Na Li ; Bin Li ; Kaisy Xinhong Ye ; Jiuyu Guo ; Jiatong Shan ; Luwen Cao ; Mei Song ; Yanyu Wang ; Tih-Shih Lee ; Andrea B Maier ; Lei Feng (2025): Targeting cognitive aging with curcumin supplementation: A systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100248
REPLY TO LETTER TO THE EDITOR: “REFINING THE EVIDENCE LINKING DIETARY DIVERSITY, GENETIC SUSCEPTIBILITY, AND DEMENTIA”
Boyue Zhao, Boyue Zhao
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Boyue Zhao ; Feng Zhang (2025): Reply to Letter to the Editor: “Refining the evidence linking dietary diversity, genetic susceptibility, and dementia”. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100246
LETTER TO THE EDITOR : REFINING THE EVIDENCE LINKING DIETARY DIVERSITY, GENETIC SUSCEPTIBILITY, AND DEMENTIA
Hongye Yao, Yangbo Lv
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CITATION:
Hongye Yao ; Yangbo Lv (2025): Letter to the Editor : Refining the evidence linking dietary diversity, genetic susceptibility, and dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100247
EDITORIAL: SERUM BDNF AND PROGRESSION TO MCI IN COGNITIVELY NORMAL OLDER ADULTS A PROSPECTIVE COHORT STUDY
Gary A. Rosenberg
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CITATION:
Gary A. Rosenberg (2025): Editorial: Serum BDNF and progression to MCI in cognitively normal older adults A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100254
PLASMA P-TAU217 PREDICTING BRAIN-WIDE TAU ACCUMULATION IN PRECLINICAL AD
Hasom Moon, Xi Chen, Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: Recently developed blood test of Alzheimer’s disease (AD) has been recognized as a promising alternative to CSF and PET, as it is noninvasive, cost-effective, and more accessible. Particularly, plasma p-tau217 shows high sensitivity in detecting β-amyloid (Aβ) and tau positivity in early AD. However, the potential value of p-tau217 in revealing Aβ and tau distribution and predicting future development has not been studied.
OBJECTIVES: We investigated the dose-response associations between p-tau217 and regional Aβ and tau measured by PET, as well as the longitudinal prediction of p-tau217 for prospective Aβ and tau accumulation measured by longitudinal PET.
DESIGN: Cross-sectional and longitudinal analyses.
SETTING: We used data in Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) study (N = 333) for primary analyses and Alzheimer’s Disease Neuroimaging Initiative (ADNI) (N = 410) for validation.
PARTICIPANTS: Cognitively unimpaired older adults (N = 333) from A4 study and cognitively unimpaired older adults (N = 222), mild cognitive impairment (N = 114), and dementia (N = 74) from ADNI.
MEASUREMENTS: Plasma p-tau217 was measured using Lilly (A4) and Fujirebio (ADNI) assays. 18-FFlorbetapir PET and 18-FFlortaucipir PET measured regional Aβ and tau.
RESULTS: Plasma p-tau217 was associated with concurrent Aβ in most cortical regions and tau in temporo-parietal cortices. Longitudinally, p-tau217 predicted brain-wide tau accumulation in widespread cortical regions in preclinical AD, but not Aβ change anywhere.
CONCLUSIONS: Plasma p-tau217 shows dose-response, brain-wide relationships with concurrent Aβ and future tau development in preclinical AD, suggesting its potential in disease trajectory monitoring and large-scale screening for individuals approaching certain biological stages of AD in clinical trials.
CITATION:
Hasom Moon ; Xi Chen ; Alzheimer’s Disease Neuroimaging Initiative (2025): Plasma p-tau217 predicting brain-wide tau accumulation in preclinical AD. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100252
EDITORIAL: EXERCISE FOR DEMENTIA PREVENTION: EVIDENCE FOR A FLEXIBLE PRESCRIPTION
Mikel Izquierdo
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CITATION:
Mikel Izquierdo (2025): Editorial: Exercise for dementia prevention: Evidence for a flexible prescription. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100249
EDITORIAL: ASTROCYTES PROVIDE A UNIQUE BIOMARKER FOR ALZHEIMER’S AND OTHER PATHOLOGIES
Eric Siemers
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CITATION:
Eric Siemers (2025): Editorial: Astrocytes provide a unique biomarker for Alzheimer’s and other pathologies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100233
PSYCHOSOCIAL STRESSORS AND COGNITIVE FUNCTION: AN ANALYSIS USING DATA FROM THE ENGLISH LONGITUDINAL STUDY OF AGEING
Jiahao Li, Natalia Ortí-Casañ, Irem Bayraktaroglu, Giulia Mozzanica, Feng Zhang, Jocelien D.A. Olivier, Ulrich L.M. Eisel
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BACKGROUND: Growing evidence suggests that psychosocial stressors—such as financial strain, caregiving responsibilities, disability, and limiting long-term illnesses—may contribute to accelerated cognitive decline in older adults. However, the heterogeneity of stressor profiles and their distinct impact on specific cognitive domains remain poorly understood.
OBJECTIVE: To examine the associations between varying burdens of psychosocial stressors and cognitive function over a 10-year period using data from the English Longitudinal Study of Ageing (ELSA).
METHODS: We used longitudinal data from wave 4 (2008–2009) to wave 9 (2018–2019) of ELSA, comprising 10,893 participants aged ≥50 years at baseline who had valid measurements of psychosocial stressors and cognitive outcomes. Psychosocial stressors—financial strain, caregiving, disability, and limiting long-term illness—were assessed as binary indicators and summed into three categories (No Stressors, One Stressor, Multiple Stressors). Cognitive function was assessed using an overall global cognition score and scores of three specific domains: memory, executive function, and orientation. Baseline associations were examined via multiple linear regression, while linear mixed-effects models evaluated longitudinal trajectories of cognitive change. All models were progressively adjusted for demographic, lifestyle, and clinical covariates.
RESULTS: At baseline, participants reporting multiple stressors (18.2 % of the sample) had significantly lower global cognitive and executive function scores compared to those with no stressors (43.3 %). Over the 10-year follow-up, a higher stress burden predicted faster declines in global cognition, memory, and executive function. These associations remained robust after adjusting for sociodemographic characteristics, health behaviors, and chronic conditions. Random intercept and random slope models yielded consistent findings, indicating a dose–response relationship between stress burden and cognitive deterioration.
CONCLUSION: Older adults experiencing multiple psychosocial stressors face an elevated risk of both lower initial cognitive function and accelerated decline over time. These findings underscore the importance of identifying and mitigating modifiable stressors—such as financial strain and caregiving demands—to potentially preserve cognitive health in later life. Interventions tailored to individuals with higher stress burdens may be especially beneficial in slowing cognitive deterioration.
CITATION:
Jiahao Li ; Natalia Ortí-Casañ ; Irem Bayraktaroglu ; Giulia Mozzanica ; Feng Zhang ; Jocelien D.A. Olivier ; Ulrich L.M. Eisel (2025): Psychosocial stressors and cognitive function: An analysis using data from the English longitudinal study of ageing. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100232
LETTER TO THE EDITOR: MONITORING OF AMYLOID RELATED IMAGING ABNORMALITIES: SWI VS T2*-GRE
Diana M. Sima, Thanh Vân Phan, Thanh Vân Phan, Wende N. Gibbs, Frederik Barkhof, Philip Scheltens, Stephen Salloway, Jeffrey Cummings, Wim Van Hecke, Dirk Smeets
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Amyloid-β–directed monoclonal antibody therapies may lead to amyloid-related imaging abnormalities (ARIA). Clinical trials that formed the basis for the ARIA radiographic severity grading scale adopted by the approved drugs’ labels utilized T2* gradient recalled echo (T2*-GRE) images for ARIA-hemorrhagic (ARIA-H) assessment. Little is known about the application of susceptibility-weighted imaging (SWI) to ARIA-H assessment. We exploited comparative studies on the usage of SWI instead of 2D T2*-GRE and simulated the impact of SWI’s higher sensitivity on the derived ARIA-H severity distribution for three approved drugs. The simulations indicated that the two sequences are not equivalent when grading ARIA-H severity and that the rate of therapy discontinuation would increase by more than 50% compared to the rates reported in the drugs’ prescribing information. This should be taken into consideration whenever SWI is applied for ARIA safety monitoring. Appropriate imaging guidelines are needed to enhance management of amyloid-β-directed antibody therapies.
CITATION:
Diana M. Sima ; Thanh Vân Phan ; Ana M. Franceschi ; Wende N. Gibbs ; Frederik Barkhof ; Philip Scheltens ; Stephen Salloway ; Jeffrey Cummings ; Wim Van Hecke ; Dirk Smeets (2025): Letter to the Editor: Monitoring of amyloid related imaging abnormalities: SWI vs T2*-GRE. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100220
ADVANCING THE SCIENCE OF RECRUITMENT FOR ALZHEIMER’S CLINICAL TRIALS: CHALLENGES AND OPPORTUNITIES
Paul Aisen, Desi Peneva, Maria-Alice Manetas, Mireille Jacobson, Dana Goldman, Niranjan Bose, Phyllis Barkman Ferrell, VK Vu, Rema Raman
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Despite recent advancements in Alzheimer’s disease therapeutics and diagnostics, significant challenges remain in accelerating participant recruitment—particularly among diverse populations—and ensuring equitable access to clinical trials. This paper summarizes discussions and recommendations from the 2024 Roundtable on Advancing the Science of Recruitment for Inclusive Alzheimer’s Disease Clinical Trials, hosted by the USC Clinical Trial Recruitment Lab (CTRL). Bringing together 40 leading experts from across the Alzheimer’s clinical trial ecosystem in the U.S., including thought leaders from academia, industry, government and philanthropy, the Roundtable examined critical barriers to inclusivity and explored emerging recruitment approaches. Discussions highlighted the need for strategies that expand patient access, remove systemic barriers, and foster inclusivity in clinical research.
CITATION:
Paul Aisen ; Desi Peneva ; Maria-Alice Manetas ; Mireille Jacobson ; Dana Goldman ; Niranjan Bose ; Phyllis Barkman Ferrell ; VK Vu, ; Rema Raman (2025): Advancing the science of recruitment for Alzheimer’s clinical trials: Challenges and opportunities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100230
TAILORING MULTIDOMAIN INTERVENTION PROGRAMS TO REDUCE COGNITIVE AND PHYSICAL DECLINE IN OLDER ADULTS: EXAMINING RURAL-URBAN DIFFERENCES IN A NATIONWIDE CLUSTER-RANDOMIZED CONTROLLED TRIAL
Min-Yin Ho, Wei-Ju Lee, Ko-Han Yen, Chih-Kuang Liang, Li-Ning Peng, Ming-Hsien Lin, Ching-Hui Loh, Fei-Yuan Hsiao, Liang-Kung Chen
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BACKGROUND: Frailty and cognitive impairment are major challenges in aging populations. Multidomain interventions targeting physical, cognitive, and nutritional health show promise; however, evidence on rural-urban differences in efficacy remains limited.
OBJECTIVES: To evaluate the impact of rural-urban disparities on the clinical efficacy of a 12-month multidomain intervention for cognitive and physical outcomes in older adults.
DESIGN: Cluster-randomized controlled trial.
SETTING: Community clusters in five cities/counties across Taiwan.
PARTICIPANTS: A total of 1082 adults aged ≥65 years from 40 community clusters were randomized to intervention or control groups.
INTERVENTION: The intervention group received a 12-month program including physical exercise (45 min/session), cognitive training (1 hour/session), and nutritional guidance (15 min/session). The control group received telephone-based health education. This trial was registered at ClinicalTrials.gov (NCT03056768)
MEASUREMENTS: Outcomes included walking speed, grip strength, physical activity (METs), frailty (CHS score), and cognitive function (MoCA), assessed at baseline, 6, and 12 months.
RESULTS: Urban participants showed significantly greater gains in visuospatial/executive function at the 12 month (rural-urban difference 0.63, 95 % CI: 0.26 -1.03), and walking speed at the 12 month (rural-urban difference 0.12 m/s, 95 % CI: 0.05 – 0.19). Rural participants demonstrated better improvements in grip strength at the 12 month (rural-urban difference -2.59 kg, 95 % CI: -3.91 - -1.27) and language function (rural-urban difference -0.38, 95 % CI: -0.68 - -0.09). Frailty reduction was more pronounced in urban areas at the 12 month (−0.21, 95 % CI: -0.38 - -0.03, p = 0.025), but showed minimal change in the rural participants.
CONCLUSION: Rural-urban disparities influence the effectiveness of multidomain interventions. Tailored strategies are needed to optimize health outcomes across diverse settings.
CITATION:
Min-Yin Ho ; Wei-Ju Lee ; Ko-Han Yen ; Chih-Kuang Liang ; Li-Ning Peng ; Ming-Hsien Lin ; Ching-Hui Loh ; Fei-Yuan Hsiao ; Liang-Kung Chen (2025): Tailoring multidomain intervention programs to reduce cognitive and physical decline in older adults: Examining rural-urban differences in a nationwide cluster-randomized controlled trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100231
EDITORIAL: BREAKING BARRIERS: DELIVERING THERAPEUTICS TO THE BRAIN IN ALZHEIMER’S DISEASE
Bart De Strooper, Philip Scheltens, Stephen Salloway
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CITATION:
Bart De Strooper ; Philip Scheltens ; Stephen Salloway (2025): Editorial: Breaking barriers: Delivering therapeutics to the brain in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100229
THE COUPLING OF GLOBAL BRAIN ACTIVITY AND CEREBROSPINAL FLUID FLOW AS A POTENTIAL PREDICTIVE MARKER OF BRAIN AMYLOID-Β ACCUMULATION
Yuya Tanaka, Koji Kamagata, Yuya Saito, Kaito Takabayashi, Rinako Iseki, Wataru Uchida, Christina Andica, Akifumi Hagiwara, Akihiko Wada, Toshiaki Akashi, Osamu Abe, Shigeki Aoki, Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: Impaired cerebrospinal fluid (CSF) clearance is thought to contribute to amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD). Global brain activity–CSF flow coupling (gBOLD–CSF coupling), measured through resting-state functional MRI, reflects CSF clearance capacity. A higher coupling value indicates weaker coupling. Its potential as a predictive marker for Aβ accumulation remains unclear.
OBJECTIVES: This study aims to determine whether weaker gBOLD–CSF coupling precedes Aβ accumulation in cognitively normal, Aβ-negative individuals and to explore its predictive potential for amyloid conversion.
DESIGN: A longitudinal observational study using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data.
SETTING: Data from ADNI-participating sites.
PARTICIPANTS: 16 cognitively normal participants, initially Aβ-negative: seven fast-converters (transitioned to Aβ-positive within two years) and nine slow-converters (remained Aβ-negative for at least two years).
MEASUREMENTS: gBOLD–CSF coupling was calculated as the Pearson correlation coefficient between global Blood-Oxygen-Level-Dependent (BOLD) and CSF inflow signals. Group differences in gBOLD–CSF coupling were analyzed, along with partial correlation analyses between gBOLD–CSF coupling and annual changes in Aβ biomarkers and cognitive scores.
RESULTS: Fast-converters showed significantly higher gBOLD–CSF coupling values, indicating weaker coupling (Cohen’s d = 1.76, p = 0.012). Coupling values positively correlated with annual changes in Aβ-PET SUVR (r = 0.594, p = 0.054) and negatively with MoCA scores (r = −0.654, p = 0.021).
CONCLUSION: Weaker gBOLD–CSF coupling precedes brain Aβ accumulation, indicating its potential as a predictive marker for amyloid conversion. Future studies should refine clinical thresholds for early intervention strategies in AD prevention.
CITATION:
Yuya Tanaka ; Koji Kamagata ; Yuya Saito ; Kaito Takabayashi ; Rinako Iseki ; Wataru Uchida ; Christina Andica ; Akifumi Hagiwara ; Akihiko Wada ; Toshiaki Akashi ; Osamu Abe ; Shigeki Aoki ; Alzheimer’s Disease Neuroimaging Initiative (2025): The coupling of global brain activity and cerebrospinal fluid flow as a potential predictive marker of brain amyloid-β accumulation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100228
IMPACT OF CARDIOVASCULAR RISK FACTORS ON PLASMA BIOMARKERS IN PREDICTION OF ALZHEIMER\'S AND CEREBROVASCULAR NEUROPATHOLOGY
Camilo Bermudez, Jeremy A. Syrjanen, Nikki H. Stricker, Alicia Algeciras-Schimnich, Naomi Kouri, Walter K. Kremers, Ronald C. Petersen, Clifford R. Jack Jr, David S. Knopman, Dennis W. Dickson, Darren M. Rothberg, Christina M. Moloney, Baayla D.C. Boon, Aivi T. Nguyen, R. Ross Reichard, Melissa E. Murray, Michelle M. Mielke, Prashanthi Vemuri, Jonathan Graff-Radford
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BACKGROUND: Plasma biomarkers for Alzheimer’s disease and neurodegeneration have shown accurate prediction of underlying neuropathology. However, chronic cardiovascular risk factors such as diabetes and hypertension are associated with plasma biomarker levels and can influence the accurate prediction of underlying neuropathologic changes.
OBJECTIVE: To understand the interaction between plasma biomarkers of Alzheimer’s disease and neurodegeneration with cardiovascular risk factors in relation to neuropathologic change in a heterogenous population to ascertain a more accurate utilization of these biomarkers.
DESIGN: Retrospective, case-control study.
SETTING: Population-based, Olmstead county, Minnesota, USA.
PARTICIPANTS: Three-hundred and fifty-one participants (aged 87.4 ± 7.5 years) with brain autopsy and antemortem plasma biomarker testing.
MEASUREMENTS: Plasma biomarker testing for Aβ42/40, p-tau181, GFAP, and NfL using Quanterix Simoa assays. Cardiovascular risk factors were quantified by a composite score of cardiovascular metabolic conditions (CMC) consisting of a binary history of diabetes, congestive heart failure, stroke, coronary artery disease, atrial fibrillation, hypertension, or dyslipidemia. Plasma biomarkers and cardiovascular metabolic conditions score were Z-scored and neuropathologic scales were binarized into high and low categories. Outcomes included elevated microvascular (Kalaria) and macrovascular (Strozyk) neuropathologic scales as well as Alzheimer’s disease neuropathologic change (ADNC), Thal phase, Braak stage, and neuritic plaque score. Multivariate logistic regression models incorporated interaction terms between plasma biomarkers and CMC while controlling for age, sex, cognitive impairment, and BMI.
RESULTS: We observed that at higher cardiovascular metabolic conditions score, the association between GFAP and overall ADNC (OR = 0.61 [0.42, 0.89]), Thal phase (OR = 0.48 [0.33, 0.71]), and Braak Stage (OR = 0.56 [0.37, 0.84]), became weaker, while the association with Strozyk score (OR = 1.65 [1.11, 2.46]) was stronger with higher CMC. Meanwhile, at higher CMC Aβ42/40 became more strongly negative with high Braak stage (OR = 0.63 [0.47, 0.85]), neuritic plaque score (OR 0.70 [0.52, 0.95]), Kalaria score (OR = 0.71 [0.57, 0.88]), and Strozyk score (OR = 0.60 [0.43, 0.83]). The association between p-tau181 and Thal phase (OR = 1.43 [1.00, 2.04]) was stronger at higher CMC while the association between p-tau181 and Strozyk score (OR = 0.47 [0.31, 0.71]) was weaker at higher CMC. There was no interaction between NfL and CMC score for any metric of neuropathologic change.
CONCLUSION: Understanding how cardiovascular risk factors can modulate plasma biomarkers is important for their interpretation with respect to underlying pathology and their clinical application in screening, diagnosis, and prognosis of neurodegenerative diseases.
CITATION:
Camilo Bermudez ; Jeremy A. Syrjanen ; Nikki H. Stricker, ; Alicia Algeciras-Schimnich ; Naomi Kouri ; Walter K. Kremers ; Ronald C. Petersen ; Clifford R. Jack Jr ; David S. Knopman ; Dennis W. Dickson ; Darren M. Rothberg ; Christina M. Moloney ; Baayla D.C. Boon ; Aivi T. Nguyen ; R. Ross Reichard ; Melissa E. Murray ; Michelle M. Mielke ; Prashanthi Vemuri ; Jonathan Graff-Radford (2025): Impact of cardiovascular risk factors on plasma biomarkers in prediction of Alzheimer's and cerebrovascular neuropathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.1002248
DOSE- AND PATTERN- PHYSICAL ACTIVITY IS ASSOCIATED WITH LOWER RISK OF DEMENTIA
Yan Wang, Fangyu Li, Shuman Cao, Jianping Jia
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BACKGROUND: The amount and pattern of physical activity that benefits cognitive health remain unclear.
METHODS: Participants from the UK Biobank cohort who had a full week of accelerometer-based moderate-to-vigorous physical activity (MVPA) and light physical activity (LPA) data were included in the analysis. The data for dementia diagnosis were collected from 2006 to 2024. Associations between the incidence of all-cause dementia, Alzheimer’s disease (AD), vascular dementia (VaD), and PA amounts and patterns were assessed using Cox proportional hazards regression models. The analysis included 1) comparing MVPA gradients with reference group performing less than 150 min/week; 2) classifying MVPA patterns as effective intensive (≥300 min/week with ≥50 % of MVPA in 1–2 days), effective regular (≥300 min/week not up to effective intensive), and ineffective (<300 min/week); 3) performing stratified analyses by age, sex, and APOE ε4 carrier status; and 4) evaluating the association between LPA and dementia risk among participants classified as ineffective MVPA levels.
RESULTS: 91,512 individuals (mean [SD] age, 56.03[7.8] years; 55.9 % female) were included. Compared with participants performing <150 min of MVPA per week, those accumulating 150–299 min/week, whether through concentrated (1–2 days) or regular pattern, did not show significantly lower dementia incidence. However, accumulating >300 min/week of MVPA was associated with a reduced risk. When stratified at 300 min/week of MVPA, hazard ratios for dementia were 0.73 (95 % CI: 0.60–0.89) for the weekend pattern and 0.79 (95 % CI: 0.64–0.98) for the regular pattern. For ineffective MVPA, engaging in >840 min/week of LPA was associated with lower dementia incidence.
CONCLUSIONS: Accumulating >300 min/week of MVPA, whether concentrated within 1–2 days or distributed evenly across the week, was associated with a decreased risk of dementia. Additionally, higher levels of LPA partially compensated for low MVPA in lowering dementia risk.
CITATION:
Yan Wang ; Fangyu Li ; Shuman Cao ; Jianping Jia (2025): Dose- and pattern- physical activity is associated with lower risk of dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100223
ADHERENCE TO AN ANTI-INFLAMMATORY DIET IS ASSOCIATED WITH LOWER ALZHEIMER’S DISEASE MORTALITY: A MODIFIABLE RISK FACTOR IN A NATIONAL COHORT
Ching-Chi Hsu, Shiow-Ing Wang, Sebastian Yu, Eric S. Lin, James Cheng-Chung Wei
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BACKGROUND: Chronic neuroinflammation contributes to Alzheimer’s disease (AD) pathogenesis, and diet is a modifiable factor influencing inflammation. The impact of an anti-inflammatory diet on AD-specific mortality remains unclear.
OBJECTIVES: To examine the association between adherence to an anti-inflammatory diet (measured as the percentage of dietary energy from anti-inflammatory foods) and AD-specific mortality, as well as all-cause mortality, in a large national cohort, and to determine whether associations differ by sex or race/ethnicity.
METHODS: We analyzed 18,795 U.S. adults (≥18 years) from the 2007–2014 National Health and Nutrition Examination Survey. Anti-inflammatory diet adherence was defined as the percentage of total energy intake from anti-inflammatory foods, categorized as 0 %, <5 %, 5–9.99 %, or ≥10 %. Outcomes were AD-specific mortality and all-cause mortality ascertained via the National Death Index. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality across intake categories, adjusting for demographic, lifestyle, and health factors. Analyses were stratified by sex, race/ethnicity, and age (≥45 years for AD mortality).
RESULTS: Participants with 0 % anti-inflammatory intake had a higher all-cause mortality risk (HR 3.82, 95 % CI 1.18–12.33) compared to those with ≥10 % intake. In the overall analysis, 0 % anti-inflammatory intake showed a trend of reduced AD-specific mortality although its did not reach statistical significance after full adjustment (HR 3.04, 95 % CI 0.74–12.46 vs. ≥10 % intake; p>0.05). Notably, the inverse association between anti-inflammatory diet and AD mortality emerged in subgroup analyses. Male participants and non-Hispanic White participants with 0 % intake had the highest AD mortality hazards (HR 12.83 and 3.77, respectively, vs. ≥10 % intake), indicating significant risk reductions with anti-inflammatory diet in these groups. In contrast, no significant associations were observed in female or non-White subgroups. Even a modest intake of anti-inflammatory foods (≥10 % of calories) was associated with lower AD mortality risk in the above subgroups and with lower all-cause mortality overall.
CONCLUSION: Greater consumption of anti-inflammatory foods was associated with lower all-cause and a trend toward lower AD-specific mortality. The observed protective effects were confined to certain subpopulations (notably men and non-Hispanic Whites). Even a small portion of the diet (10 % of calories) being anti-inflammatory was linked to reduced mortality risk in these groups, suggesting that achievable dietary changes could have an impact. These findings support modifying dietary content is a practical, low-cost intervention that could mitigate neuroinflammation to reduce AD mortality risk.
CITATION:
Ching-Chi Hsu ; Shiow-Ing Wang ; Sebastian Yu ; Eric S. Lin ; James Cheng-Chung Wei (2025): Adherence to an anti-inflammatory diet is associated with lower Alzheimer’s disease mortality: A modifiable risk factor in a national cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100221
EDITORIAL: PHYSICAL ACTIVITY AND ALZHEIMER’S DISEASE: A CALL FOR EVIDENCE INCORPORATION
Juan Luis Sánchez-Sánchez, Philipe de Souto Barreto
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CITATION:
Juan Luis Sánchez-Sánchez ; Philipe de Souto Barreto (2025): Physical activity and Alzheimer’s disease: a call for evidence incorporation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100225
HOUSEHOLD FUEL USE AND MOTORIC COGNITIVE RISK SYNDROME AMONG OLDER ADULTS: EVIDENCE FROM COHORT STUDY AND LIFE COURSE ANALYSIS
Guanghui Cui, Shaojie Li, Weiwei Li, Xuezhi Zhang
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BACKGROUND: Motoric cognitive risk syndrome (MCRS) is a predementia syndrome, and its prevention is valuable for reducing the incidence of dementia. However, few studies have focused on the association between indoor air pollution caused by household cooking fuel use and MCRS. This study aimed to investigate whether clean cooking fuel use is associated with reduced MCRS risk and whether the timing of clean fuel adoption across the life span is associated with MCRS prevalence.
METHODS: We used data from the China Health and Retirement Longitudinal Study. A prospective cohort analysis (n = 4251) examined baseline fuel use (2011) and incident MCRS over four years. A cross-sectional life course analysis (n = 6964) linked retrospective fuel use histories (2014 life history survey) to MCRS status in 2015. Modified Poisson regression was used to estimate relative risks (RRs) and 95 % confidence intervals (CIs), adjusting for covariates.
RESULTS: In the cohort study, clean fuel use at baseline was associated with a reduced risk of MCRS (RR = 0.76; 95 % CI: 0.61–0.96). Lower risks were also observed among participants who transitioned from solid to clean fuels and those who consistently used clean fuels. In the life course analysis, clean fuel adoption in early or middle adulthood was linked to lower MCRS prevalence.
CONCLUSION: Clean fuel use for cooking and transitioning from solid to clean fuels decreases MCRS risk among older adults. Moreover, earlier adoption of clean cooking fuels is associated with a lower prevalence of MCRS in later life.
CITATION:
Guanghui Cui ; Shaojie Li ; Weiwei Li ; Xuezhi Zhang (2025): Household fuel use and motoric cognitive risk syndrome among older adults: Evidence from cohort study and life course analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100227
BRIDGING THE GAP: A CONVERSION FRAMEWORK FOR CDR-SB AND MOCA SCORES IN ALZHEIMER\'S DISEASE AND RELATED DEMENTIA
Babak Haji, Quanwu Zhang, Amir Abbas Tahami Monfared
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BACKGROUND: Accurate assessment of cognitive impairment is essential to effective Alzheimer’s disease (AD) management and research. However, the absence of validated methods to translate scores between widely used instruments—such as the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) in trials and the Montreal Cognitive Assessment (MoCA) in clinical practice—poses a significant barrier. This limits data harmonization, impedes cross-study comparability, and complicates the integration of clinical and research evidence. Bridging this gap is critical for consistent staging, longitudinal monitoring, and data-driven decision-making in AD and related dementias.
OBJECTIVES: To develop and validate bidirectional score conversion tables between CDR-SB and MoCA using a large, diverse cohort spanning the full spectrum of cognitive function.
DESIGN: Retrospective, cross-sectional analysis using equipercentile equating with log-linear smoothing. Optimal smoothing parameters were selected by minimizing mean squared error, Akaike Information Criterion, and Bayesian Information Criterion. Concordance was assessed using Spearman’s rank correlation and Bland-Altman plots.
SETTING: National Alzheimer’s Coordinating Center (NACC), aggregating standardized assessments from 35 U.S.-based Alzheimer’s Disease Research Centers.
PARTICIPANTS: 23,717 individuals (59,871 visits) with same-day CDR-SB and MoCA assessments from January 2015 to September 2024, spanning normal cognition, mild cognitive impairment (MCI), and dementia.
INERVENTION: None; this was a secondary analysis of existing data.
MEASUREMENTS: Primary measures included CDR-SB (0–18; higher = greater impairment) and MoCA (0–30; higher = better cognition). Bidirectional crosswalk tables were derived using equipercentile equating.
RESULTS: CDR-SB and MoCA scores showed strong inverse correlation (Spearman’s ρ = –0.68; p < 0.001). Crosswalk tables demonstrated good agreement across the cognitive spectrum and performed consistently in the full cohort and an AD-specific subgroup.
CONCLUSIONS: This study provides the first validated, bidirectional CDR-SB–MoCA crosswalk, supporting data harmonization and consistent interpretation of cognitive severity across research and clinical settings.
CITATION:
Babak Haji ; Quanwu Zhang ; Amir Abbas Tahami Monfared (2025): Bridging the gap: A conversion framework for CDR-SB and MoCA scores in Alzheimer's disease and related dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
TRAJECTORIES OF CARDIORESPIRATORY FITNESS MEASURED BY METABOLIC EQUIVALENTS AND THE RISK OF ALZHEIMER\'S AND RELATED DEMENTIAS
Edward Zamrini, Yan Cheng, Peter Kokkinos, Charity J Morgan, Charles Faselis, Helen M Sheriff, Yijun Shao, Xuemei Sui, Ali Ahmed, Qing Zeng
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BACKGROUND: Higher fitness levels have been reported to protect against Alzheimer's Disease and Related Dementias (ADRD). However, the association between changes in fitness over time and ADRD risk remains unknown. This study aims to identify clusters of metabolic equivalents (METs) trajectories and examine their correlation with incident ADRD.
METHODS: A retrospective cohort study was conducted among Veterans with ≥3 standardized exercise treadmill tests (ETT) between 2000 and 2017. The exposure was change in fitness expressed in metabolic equivalents (METs). METs are based on treadmill speed, grade, and time. One MET is equivalent to 3.5 ml per kg of body weight per minute. The outcome was incident ADRD after the final ETT test, identified by diagnosis codes. Standardized METs scores were generated using mean and standard deviation for each age and sex stratum. Latent class growth analysis (LCGA) identified trajectory clusters. We assessed the association between clusters and ADRD using unadjusted Kaplan-Meier curves (overall and by age groups) and a multivariate Cox regression model adjusted for baseline characteristics at the first ETT.
RESULTS: A total of 75,851 veterans were included. The average number of ETTs was 4.0 ± 1.8, with the average time gap of 6.5 ± 3.8 years between first and last test. We identified five trajectory clusters: Group 1 (n = 22,485), Group 2 (n = 22,694), Group 3 (n = 6691), Group 4 (n = 19,386), and Group 5 (n = 4595). All groups, except for Group 3, showed a stable and slight improvement or decline over time, differing only in their initial standardized METs scores: Group 5 had the highest initial score, Group 1 had the lowest initial score, while Group 3 started out with a score almost as high as Group 4 and dropped to as low as Group 1. Compared to Group 1, Group 3 had a 12 % reduced risk of developing ADRD (HR = 0.88; 95 % CI: 0.77 – 1.01; p = 0.0660), with a greater reduction than Group 2 (10 %) but less than Group 4 (17 %) or Group 5 (24 %).
DISCUSSION: Our findings underscore the potential benefits of maintaining fitness to reduce the risk of ADRD with age. Although declining fitness levels are associated with an increased risk, the initial higher baseline fitness provides a degree of ongoing protection against ADRD.
CITATION:
Edward Zamrini ; Yan Cheng ; Peter Kokkinos ; Charity J Morgan ; Charles Faselis ; Helen M Sheriff ; Yijun Shao ; Xuemei Sui ; Ali Ahmed ; Qing Zeng (2025): Trajectories of Cardiorespiratory Fitness Measured by Metabolic Equivalents and the Risk of Alzheimer's and Related Dementias. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100222
ESTIMATION OF THE VALUE-BASED PRICE OF A BLOOD TEST FOR ALZHEIMER’S DISEASE PATHOLOGY IN PRIMARY AND SPECIALTY CARE IN THE U.S.
Soeren Mattke, Jiahe Chen, Mark Hanson, Kim G. Johnson, Cara Leahy, David A. Merrill, Victoria Shada, Jorge G. Ruiz
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BACKGROUND: Blood tests for the pathology of Alzheimer’s disease (AD) are emerging as alternative to amyloid PET scans and analysis of cerebrospinal fluid. (CSF). However, their economic value, which depends on test accuracy as well as effect on clinical decision-making, remains unclear.
METHODS: We use a Markov model to estimate the value-based price of a blood test with sensitivity of 88 % and specificity of 89 %, if labeled for triage and confirmation of the AD pathology in primary and specialty care. The value-based price was defined as price of the test, at which overall diagnostic cost per true positive case of early-stage AD would equate that under standard of care (identification in primary care and referral to specialty care based on the results of a brief cognitive test). Assumptions for the effect of test use on clinical decisions came from a structured expert consultation process.
RESULTS: If used in primary care, the value-based price would be $290 for a triage and $1150 for a confirmatory test, respectively, as use of PET or CSF testing would decline by 47 % and 86 %, respectively. If used in specialty care, i.e., after confirmation of early-stage cognitive impairment, the overall number of blood tests would decline. Consequently, the value-based price would increase to $450 for a triage test and $1950 for a confirmatory test.
CONCLUSION: The results project substantial cost savings from implementing a blood test for AD pathology within the diagnostic pathway based on modeling results, which future research should confirm with actual data.
CITATION:
Soeren Mattke ; Jiahe Chen ; Mark Hanson ; Kim G. Johnson ; Cara Leahy ; David A. Merrill ; Victoria Shada ; Jorge G. Ruiz (2025): Estimation of the value-based price of a blood test for Alzheimer’s disease pathology in primary and specialty care in the U.S.. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100219
SALIVARY LEVELS OF AMYLOID BETA REFLECT BRAIN AMYLOID BETA BURDEN IN COGNITIVELY-NORMAL OLDER ADULTS
Alison R. Bamford, Jenna N. Adams, Soyun Kim, Lisa M. Taylor, Nandita Tuteja, Liv C. McMillan, Negin Sattari, Ivy Y. Chen, Miranda G. Chappel-Farley, Yuritza Escalante, Alyssa L. Lawrence, Novelle J. Meza, Destiny E. Berisha, Abhishek Dave, Rond Malhas, Mark Mapstone, Bryce A. Mander, Michael A. Yassa, Elizabeth A. Thomas
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BACKGROUND: Amyloid beta (Aβ) plaque burden, as measured by positron emission tomography (PET), is increasingly being used as a biomarker for Alzheimer's disease (AD) as well as a screening or monitoring tool for clinical trials with amyloid-lowering drugs. However, PET imaging is expensive, invasive and not widely available for all patients, necessitating alternative means to assess brain Aβ accumulation.
OBJECTIVES: In this study, we measured levels of Aβ42, Aβ40 and Aβ38 in saliva samples from cognitively unimpaired older adults (n=93; 61.7 % female; mean age = 70.1 ± 6.6 years) using the Mesoscale Discovery platform, carefully considering preanalytical variables, including timing of sample collection, blood contamination and sample concentration. We next determined the relationships between Aβ peptide levels and Aβ plaque burden within the brain, determined using 18F-florbetapir (FBP) PET.
RESULTS: We found that salivary levels of Aβ38 and Aβ42, but not Aβ40 nor the Aβ42/Aβ40, were significantly positively correlated with the global mean FBP standardized uptake value ratio (SUVR), before and after adjusting for age, sex and time of day of saliva sample collection (r=0.523/0.544, p=0.001/0.002 and r=0.316/0.32, p=0.031/0.044, for Aβ38 and Aβ42, respectively). Similar results were observed when Aβ values were analyzed as a ratio to the total protein levels in each sample and when tested in saliva samples that were collected during a restricted morning time window. Using composite regions which represent cortical regions vulnerable to Aβ accumulation in early, intermediate, and late stages of AD, we found that Aβ38 showed the most robust correlation with FBP SUVRs from early-accumulating brain regions (r=0.510; p<0.001). In contrast to the observed effects in saliva, plasma levels of Aβ42 measured from a subset of the participants showed a significant negative correlation to mean FBP SUVR. Using logistic regression analysis to determine whether any salivary Aβ species could predict brain Aβ burden, we found that salivary levels of Aβ38 in combination with age, sex, sample timing and APOE genotype could predict Aβ-PET positivity with an area under the curve = 0.950 (95 % confidence interval, 0.876–1.0; p<0.0001).
CONCLUSIONS: Our findings suggest that salivary Aβ38 and/or Aβ42 could have relevance as a non-invasive, and more widely applicable biomarker, for utility in clinical studies on AD.
CITATION:
Alison R. Bamford ; Jenna N. Adams ; Soyun Kim ; Lisa M. Taylor ; Nandita Tuteja ; Liv C. McMillan ; Negin Sattari ; Ivy Y. Chen ; Miranda G. Chappel-Farley ; Yuritza Escalante ; Alyssa L. Lawrence ; Novelle J. Meza ; Destiny E. Berisha ; Abhishek Dave ; Rond Malhas ; Mark Mapstone ; Bryce A. Mander ; Michael A. Yassa ; Elizabeth A. Thomas ; (2025): Salivary levels of amyloid beta reflect brain amyloid beta burden in cognitively-normal older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100216
THE PATIENT PATHWAY FOR MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE IN ASIA: CURRENT PRACTICES, BARRIERS, AND EXPERT RECOMMENDATIONS FOR OPTIMIZATION
Seong Hye Choi, SangYun Kim, Paulus Anam Ong, Ai Vyrn Chin, Jacqueline Dominguez, Jacqueline Dominguez, Vorapun Senanarong, Chaur-Jong Hu, Manjari Tripathi, Vincent Mok, Gandan Jiang, Amitabh Dash
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BACKGROUND: The age-standardized prevalence of Alzheimer’s disease in Asia has increased rapidly in recent years. Disease-modifying treatments that can slow disease progression are now becoming available for patients with early-stage Alzheimer’s disease, including those with mild cognitive impairment. However, challenges in diagnosis and assessment for these patients remain.
OBJECTIVES: This study characterized the care pathway for mild cognitive impairment due to Alzheimer’s disease in Asia, including barriers to care, and considered the future treatment landscape, with the aim of making recommendations for optimizing the care pathway in readiness for the availability of new disease-modifying treatments.
DESIGN: Qualitative study based on semi-structured interviews.
SETTING: Interviews were conducted with physicians in general/tertiary hospitals in Hong Kong, India, Indonesia, Korea, Malaysia, the Philippines, Singapore, Taiwan, and Thailand. Physicians from mainland China and Japan were not included.
PARTICIPANTS: Physicians managing patients with mild cognitive impairment.
MEASUREMENTS: Number and/or proportion of participants providing a given response, and numerical estimates provided by interview participants.
RESULTS: Forty-four physicians, primarily neurologists (n = 31; 70.5 %), were interviewed. Participants managed a median of 67.5 patients with mild cognitive impairment per month, of whom 24.0–87.5 % had mild cognitive impairment due to Alzheimer’s disease. Clinical investigations routinely comprised brief neuropsychological assessments, such as the Mini-Mental State Examination (n = 41), as well as neurological tests (n = 39) and magnetic resonance imaging (n = 40). Except in Korea, comprehensive neuropsychological test batteries and amyloid positron emission tomography were seldom conducted in Asia. Most patients with mild cognitive impairment due to Alzheimer’s disease were treated with nootropics and/or acetylcholinesterase inhibitors (Korea, 96 %; all other regions, 69 %), and almost all were recommended a non-pharmacological treatment (Korea, 93 %; all other regions, 100 %). Detection of mild cognitive impairment due to Alzheimer’s disease was considered prompt in Korea but suboptimal in other regions (n = 16) owing to low disease awareness among patients. Barriers to assessment and diagnosis included delayed healthcare visits for initial assessment (n = 7), neuroimaging backlogs (n = 6), and insufficient neuropsychology resources (n = 13). Access to amyloid biomarker tests, including amyloid positron emission tomography, cerebrospinal fluid analysis, and blood tests, was limited in regions other than Korea.
CONCLUSIONS: The survey findings showed that screening and diagnostic processes for mild cognitive impairment due to Alzheimer’s disease in Asia require further optimization. Efforts should also be made to educate patients and caregivers, improve the diagnostic capabilities of primary and secondary healthcare providers, and reinforce cognitive screening services. The provision and reimbursement of confirmatory tests of amyloid burden should be expanded across the region to facilitate access to innovative disease-modifying therapies.
CITATION:
Seong Hye Choi ; SangYun Kim ; Paulus Anam Ong ; Ai Vyrn Chin ; Jacqueline Dominguez ; Christopher Li-Hsian Chen ; Vorapun Senanarong ; Chaur-Jong Hu ; Manjari Tripathi ; Vincent Mok ; Gandan Jiang ; Amitabh Dash (2025): The patient pathway for mild cognitive impairment due to Alzheimer’s disease in Asia: Current practices, barriers, and expert recommendations for optimization. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100215
UTILITY OF PLASMA GFAP AS A SECONDARY ENDPOINT FOR CLINICAL TRIALS IN ALZHEIMER’S DISEASE
Sarah Abbas, Pamela C. L Ferreira, Bruna Bellaver, Guilherme Povala, Guilherme Povala, Cristiano Schaffer Aguzzoli, Hussein Zalzale, João Pedro Ferrari-Souza, Douglas T. Leffa, Firoza Z. Lussier, Carolina Soares, Guilherme Bauer-Negrini, Markley Silva Oliveira-Junior, Matheus Scarpatto Rodrigues, Pampa Saha, Emma Ruppert, Marina Scop Medeiros, Cécile Tissot, Joseph Therriault, Nesrine Rahmouni, Stijn Servaes, Andrea L. Benedet, Nicholas J. Ashton, Dana L. Tudorascu, Serge Gauthier, Helmet Karim, Chang Hyung Hong, Hyun Woong Roh, Eduardo R Zimmer, Thomas K. Karikari, Henrik Zetterberg, Kaj Blennow, Anum Saeed, Sang Joon Son, Pedro Rosa-Neto, Tharick Pascoal, for Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: Clinical trials have recently incorporated plasma glial fibrillary acidic protein (GFAP) as an exploratory endpoint. To include plasma GFAP as a secondary endpoint, it is essential to characterize its longitudinal progression in target populations.
OBJECTIVE: To evaluate the potential use of plasma GFAP changes as a secondary endpoint in Alzheimer’s disease trials.
METHODS: We longitudinally evaluated plasma GFAP in individuals with amyloid-beta (Aβ)-PET scans at baseline in three well-characterized cohorts. Cox proportional hazards regression tested the association between changes in plasma GFAP and cognitive function. Analysis of the 95 % confidence interval of annualized change in plasma GFAP provided statistical inference for a significant longitudinal change. Effect size was calculated as the group mean divided by the standard deviation (SD). We estimated the sample size needed to test a 25% drug effect with 80% power on reducing changes in GFAP.
RESULTS: We assessed 487 individuals [176 cognitively unimpaired (CU; 29% Aβ positive) and 311 cognitively impaired (CI; 51% Aβ positive)] with some degree of cerebrovascular disease (Fazekas 1–3), over a mean (SD) follow-up of 1.84 (0.46) years. Changes in plasma GFAP were significantly associated with worsening in Clinical Dementia Rating sum of boxes (CDR-SB) score across the population (p < 0.0001). In CU, only Aβ positive individuals showed significant changes in GFAP (p < 0.001). On the other hand, both CI Aβ positive and negative individuals showed longitudinal progression in GFAP levels (p < 0.0001). The effect size of changes in plasma GFAP was higher in CU Aβ positive (0.44), followed by CI Aβ positive (0.42) and CI Aβ negative (0.38). Clinical trials focusing on CU Aβ positive would require 1320 individuals per study arm, while focusing on CI Aβ positive would require 1440 individuals per study arm.
CONCLUSION: Plasma GFAP increased in parallel with cognitive decline, making it a candidate for monitoring disease progression in trials aimed at mitigating cognitive deterioration. Although Aβ positivity significantly accelerated GFAP progression, the fact that GFAP was increased in CI Aβ negative with cerebrovascular disease supports its potential use as a secondary endpoint in this population as well.
CITATION:
Sarah Abbas ; Pamela C. L Ferreira ; Bruna Bellaver ; Guilherme Povala ; Francieli Rohden ; Cristiano Schaffer Aguzzoli ; Hussein Zalzale ; João Pedro Ferrari-Souza ; Douglas T. Leffa ; Firoza Z. Lussier ; Carolina Soares ; Guilherme Bauer-Negrini ; Markley Silva Oliveira-Junior ; Matheus Scarpatto Rodrigues ; Pampa Saha ; Emma Ruppert ; Marina Scop Medeiros ; Cécile Tissot ; Joseph Therriault ; Nesrine Rahmouni ; Stijn Servaes ; Andrea L. Benedet ; Nicholas J. Ashton ; Dana L. Tudorascu ; Serge Gauthier ; Helmet Karim ; Chang Hyung Hong ; Hyun Woong Roh ; Eduardo R Zimmer ; Thomas K. Karikari ; Henrik Zetterberg ; Kaj Blennow ; Anum Saeed ; Sang Joon Son ; Pedro Rosa-Neto ; Tharick Pascoal ; for Alzheimer’s Disease Neuroimaging Initiative (2025): Utility of plasma GFAP as a secondary endpoint for clinical trials in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100205
BISPECIFIC BRAIN-PENETRANT ANTIBODIES FOR TREATMENT OF ALZHEIMER’S DISEASE
Dag Sehlin, Greta Hultqvist, Wojciech Michno, Ximena Aguilar, Amelia D Dahlén, Enrica Cerilli, Nadja M Bucher, Sara Lopes van den Broek, Stina Syvänen
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The emerging class of bispecific antibodies represents a significant advancement in Alzheimer’s disease (AD) immunotherapy by addressing the limited brain concentrations achieved with conventional monoclonal antibodies. The majority of bispecific antibodies developed for AD treatment utilize transferrin receptor (TfR1)-mediated transcytosis to enhance blood-brain barrier (BBB) penetration, resulting in higher and more uniform brain concentrations compared to conventional antibodies. This improved delivery has demonstrated superior efficacy in reducing brain amyloid-beta (Aβ) burden. Additionally, TfR1-mediated delivery may help mitigate adverse effects such as amyloid-related imaging abnormalities (ARIA). This is likely achieved by a reduction in antibody accumulation at vascular Aβ deposits, resulting from the combined effects of lower dosing and a different brain entry route when using bispecific antibodies. Besides targeting Aβ, bispecific antibodies have been engineered to address other key pathological features of AD, including tau pathology and neuroinflammatory targets, which are critical drivers of disease progression. These antibodies also show promise in diagnostic applications, particularly as radioligands for antibody-based positron emission tomography (immunoPET), leveraging their rapid brain delivery and efficient and specific target engagement. Moreover, the principles of bispecific antibody technology have been adapted for use beyond immunotherapy. The incorporation of TfR1-binding domains into enzymes, antisense oligonucleotides, or viral vectors such as adeno-associated viruses broadens their therapeutic potential. These approaches may enable more efficient treatment strategies, not only for AD but also for other neurological disorders, by facilitating the delivery of diverse therapeutic agents across the BBB.
CITATION:
Dag Sehlin ; Greta Hultqvist ; Wojciech Michno ; Ximena Aguilar ; Amelia D Dahlén ; Enrica Cerilli ; Nadja M Bucher ; Sara Lopes van den Broek ; Stina Syvänen (2025): Bispecific brain-penetrant antibodies for treatment of Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
CEREBROVASCULAR DISEASE IN ALZHEIMER\'S DISEASE: BRAIN STRUCTURE AS A CRITICAL MEDIATOR OF COGNITIVE DECLINE
Chao Tang, Yaqi Ding, Jiaxin Yang, Dian He
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BACKGROUND: The co-occurrence of Alzheimer's disease and cerebrovascular disease is increasingly prevalent in aging populations, yet the mechanisms of their interaction remain incompletely understood. This study aims to investigate the associations between CVD and AD and their composite effects on cognitive function, identifying key mediating pathways in these relationships.
METHODS: Participants underwent standardized clinical evaluations, detailed neuropsychological testing, and comprehensive neuropathological examinations. Structural equation modeling with multiple mediation analyses was employed to disentangle direct and indirect effects of vascular pathology on cognition and identify key mediating pathways. Relationships between specific cognitive domain assessments and whole brain and hippocampal volumes were analyzed, while interactions between traditional AD biomarkers (amyloid, tau) and vascular factors were examined.
RESULTS: CVD substantially increased AD risk. Structural equation modeling revealed that vascular factors influence cognitive performance primarily through hippocampal atrophy, APOE genotype, and cerebral atrophy. Participants with concomitant AD +CVD pathology displayed a distinctive hybrid pattern of brain-cognition relationships, with stronger correlations between hippocampal atrophy and cognitive performance compared to pure AD or CVD cases. Pathway-specific analysis demonstrated that hippocampal atrophy served as the strongest mediator of vascular effects on cognition, followed by cerebral atrophy and APOE genotype.
CONCLUSION: Our findings demonstrate that cerebrovascular disease significantly increases the risk of Alzheimer's disease and substantially influences its clinical expression through multiple pathways, with structural brain changes serving as critical mediators of vascular effects on cognition. These results highlight the importance of addressing vascular health as an integral component of strategies to prevent and treat Alzheimer's disease and related cognitive disorders.
CITATION:
Chao Tang ; Yaqi Ding ; Jiaxin Yang ; Dian He (2025): Cerebrovascular disease in Alzheimer's disease: Brain structure as a critical mediator of cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100209
SERUM BDNF AND PROGRESSION TO MCI IN COGNITIVELY NORMAL OLDER ADULTS: A PROSPECTIVE COHORT STUDY
Kyungtae Kim, Min Soo Byun, Dahyun Yi, Joon Hyung Jung, Bo Kyung Sohn, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Yun-Sang Lee, Yu Kyeong Kim, Kwangsik Nho, Dong Young Lee, for the KBASE Research Group
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BACKGROUND: Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the mammalian brain. Preclinical studies suggest that BDNF influences the pathophysiology of Alzheimer's disease. In humans, higher blood BDNF levels have been associated with a lower risk of dementia. However, the relationship between serum BDNF levels and the progression to mild cognitive impairment (MCI) in cognitively normal (CN) individuals remains uncertain.
OBJECTIVES: To examine whether higher serum BDNF levels in CN older adults are associated with a reduced incidence of MCI over a 4-year follow-up period and to identify potential moderators of this relationship.
DESIGN: Longitudinal analyses were conducted using follow-up data from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort study. Data were collected from January 1, 2014, to May 31, 2021, and analyzed from May 1, 2023, to September 30, 2023.
SETTING: Community and memory clinic setting.
PARTICIPANTS: A total of 274 CN older adults aged 55–90 years were included at baseline.
MEASUREMENT: Progression to MCI over the 4-year follow-up period.
RESULTS: Among the 274 participants, 26 developed MCI during follow-up. The high BDNF group had a significantly lower incidence of MCI compared to the low BDNF group (hazard ratio [HR], 0.27; 95 % confidence interval [CI], 0.11–0.69; P = 0.006). This association persisted even after adjusting for BDNF Val66Met polymorphism, amyloid PET positivity, vascular risk factors, cholesterol levels, triglycerides, homocysteine, BMI, smoking, alcohol, TBI history, CES-D, and MMSE scores (HR, 0.14; 95 % CI, 0.05–0.40; P < 0.001). Subgroup analyses further revealed that the association was significant only in women (HR, 0.12; 95 % CI, 0.03–0.48; P = 0.002), individuals aged <75 years (HR, 0.16; 95 % CI, 0.03–0.77; P = 0.022), those with less than a college degree (HR, 0.23; 95 % CI, 0.07–0.74; P = 0.013), and amyloid PET-negative (HR, 0.29; 95 % CI, 0.11–0.72; P = 0.014) individuals.
CONCLUSIONS: These findings suggest a protective role of BDNF against clinical progression to MCI in cognitively healthy older individuals. This effect appears to be more prominent in women, as well as in relatively younger, less educated, and amyloid PET-negative individuals.
CITATION:
Kyungtae Kim ; Min Soo Byun ; Dahyun Yi ; Joon Hyung Jung ; Bo Kyung Sohn ; Gijung Jung ; Hyejin Ahn ; Jun-Young Lee ; Yun-Sang Lee ; Yu Kyeong Kim ; Kwangsik Nho ; Dong Young Lee ; for the KBASE Research Group (2025): Serum BDNF and progression to MCI in cognitively normal older adults: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100210
ASSOCIATION OF MULTIMORBIDITY AND DISEASE CLUSTERS WITH NEUROIMAGING AND COGNITIVE OUTCOMES IN UK BIOBANK
Shehab Uddin Al Abid, Catherine M Calvin, Danial Qureshi, Michele Veldsman, El?bieta Ku?ma, Thomas J. Littlejohns
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BACKGROUND: The relationship between multimorbidity, particularly disease clusters, with neuroimaging and cognitive outcomes that typically manifest prior to clinical diagnosis of dementia, remains understudied. This study investigated whether multimorbidity is associated with dementia-related neuroimaging and cognitive outcomes in the UK Biobank cohort.
METHODS: This cross-sectional study used data from UK Biobank participants who attended imaging assessments between 2014–2023, and were free from neurological conditions, including dementia. Multimorbidity was defined as the coexistence of two or more long-term conditions, selected from a standardised criteria of 39 conditions. Latent class analyses were used to identify disease clusters. Neuroimaging outcomes were measured using magnetic resonance imaging, and cognition was assessed by seven tests measuring different cognitive domains. Multivariable linear regression was used to assess the association between multimorbidity and disease clusters with neuroimaging and cognitive outcomes.
RESULTS: A total of 43,160 participants were included (mean [standard deviation] age, 64.2 [7.7] years, 53.1 % female). Multimorbidity was present among 14,339 (33.2 %) participants, and was associated with reduced grey matter volume, total brain volume, left hippocampal volume, increased cerebrovascular pathology as well as reduced domain-specific cognitive function. A strong dose-response relationship was observed with the increasing number of multimorbid conditions across these outcomes. A disease cluster driven by cardiometabolic conditions was consistently associated with poorer brain health across all outcomes. Disease clusters driven by respiratory, mental health and other conditions showed less consistent associations.
CONCLUSIONS: Multimorbidity was strongly associated with poorer brain health, particularly within the cardiometabolic disease cluster. Given that UK Biobank participants are, on average, healthier than the general population, future studies in more diverse and representative cohorts would be valuable.
CITATION:
Shehab Uddin Al Abid ; Catherine M Calvin ; Danial Qureshi ; Michele Veldsman ; Elżbieta Kuźma ; Thomas J. Littlejohns (2025): Association of multimorbidity and disease clusters with neuroimaging and cognitive outcomes in UK Biobank. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100208
COMPARATIVE EFFICACY OF COGNITIVE TRAINING MODALITIES IN COGNITIVE IMPAIRMENT: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
Li-bing Liang, Shan Wang, Kun-peng Li, Cai-qin Wu
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BACKGROUND: Cognitive training is a widely utilized non-pharmacological intervention to enhance cognitive performance in individuals with cognitive impairment. Despite its potential, significant ambiguity remains regarding its definition, optimal modalities, and design parameters. It remains unclear which types of cognitive training are relatively optimal for different levels of cognitive impairment or how intervention designs can maximize therapeutic benefits.
OBJECTIVES: This systematic review and network meta-analysis aimed to compare the effects of various cognitive training modalities on cognitive, psychological, and quality-of-life outcomes in individuals with cognitive impairment. Additionally, it sought to identify optimal intervention approaches, clarify key design parameters, and examine critical factors influencing treatment efficacy.
METHODS: A comprehensive search was conducted across 12 databases from the establishment of the database until October 24, 2024, to identify eligible randomized controlled trials (RCTs) evaluating cognitive training interventions. Data were analyzed using pairwise meta-analysis and network meta-analysis in Review Manager 5.4 and Stata 18.
RESULTS: Totally 43 RCTs were included. Pairwise meta-analysis revealed that cognitive strategy training demonstrated superior to active control (AC) or passive control (PC) in improving language function, immediate memory, depressive symptoms and quality of life. However, no significant effects were detected regarding cognitive impairment severity, delivery format, interventionist expertise level, training duration, or control type. Network meta-analysis further identified reminiscence therapy as the most pronounced effective intervention for improving global cognition across all stages of cognitive impairment.
CONCLUSIONS: Reminiscence therapy has been demonstrated as a relatively optimal cognitive training modality for enhancing cognitive function in individuals with varying levels of cognitive impairment. Future studies should prioritize longitudinal investigations to validate the durability of therapeutic benefits and incorporate neuroimaging and biomarker analyses to elucidate underlying mechanisms. High-quality RCTs remain imperative to strengthen the evidence base and evaluate the consistency of effects across diverse cognitive training interventions.
CITATION:
Li-bing Liang ; Shan Wang ; Kun-peng Li ; Cai-qin Wu (2025): Comparative efficacy of cognitive training modalities in cognitive impairment: A systematic review and network meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100207
LOWER BASELINE AMYLOID BETA BURDEN IS ASSOCIATED WITH GREATER PERCENT OF AMYLOID BETA POSITRON EMISSION TOMOGRAPHY REDUCTION AND BETTER CLINICAL OUTCOMES IN THE ADUCANUMAB PHASE 3 TRIALS ENGAGE AND EMERGE IN EARLY ALZHEIMER\'S DISEASE
Jackson Burton, Holly M. Brothers, R. Matthew Hutchison, Jennifer Murphy, Tao Sun, Gersham Dent, Gioacchino Curiale, Ken Kowalski
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BACKGROUND: Aducanumab is a human immunoglobulin G1 anti-amyloid beta antibody for early-stage Alzheimer’s disease. After the discontinuation of the aducanumab clinical program and market withdrawal, the Phase 3 data were further assessed to characterize the relationship between baseline amyloid beta load, degree of amyloid beta removal, and subsequent clinical outcomes to provide context for future research.
OBJECTIVES: This analysis leveraged modelling techniques to impute missing amyloid beta positron emission tomography values and better understand the relationship between baseline amyloid beta positron emission tomography status, amyloid beta positron emission tomography reduction, and clinical outcomes in the aducanumab Phase 3 ENGAGE and EMERGE (NCT02477800/NCT02484547) studies.
DESIGN: Exploratory data analysis.
SETTING: A previously developed model which characterized the relationship between aducanumab exposure and amyloid beta positron emission tomography standard uptake value ratio was updated to impute centiloid values for participants not enrolled in the amyloid beta positron emission tomography substudy. Additional clinically-relevant variables were also summarized.
PARTICIPANTS: 1876 participants with baseline amyloid beta positron emission tomography and clinical endpoints in a pooled ENGAGE/EMERGE dataset at week 78.
INTERVENTION: Aducanumab.
MEASUREMENTS: Amyloid burden measured by centiloids and clinical endpoints.
RESULTS: In older participants whose baseline amyloid beta burden is lower than the average trial population, exposure to aducanumab provides greater clinical benefit across cognitive and functional endpoints.
CONCLUSIONS: The relationship between baseline amyloid beta load and treatment benefit in a large population after exposure to an amyloid beta–directed antibody provides insight into which subpopulations are likely to benefit from this class of treatment.
CITATION:
Jackson Burton ; Holly M. Brothers ; R. Matthew Hutchison ; Jennifer Murphy ; Tao Sun ; Gersham Dent ; Gioacchino Curiale ; Ken Kowalski (2025): Lower baseline amyloid beta burden is associated with greater percent of amyloid beta positron emission tomography reduction and better clinical outcomes in the aducanumab Phase 3 trials ENGAGE and EMERGE in early Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100202
LETTER TO THE EDITOR: COMMENT ON \"HEARING LOSS, DIET, AND COGNITIVE DECLINE: INTERCONNECTIONS FOR DEMENTIA PREVENTION\"
Cuiqing Zhao, Jian Gong, Jia Huang
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CITATION:
Cuiqing Zhao ; Jian Gong ; Jia Huang (2025): Letter to the Editor: Comment on "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.2025.100189
CAUSAL RELATIONSHIP AND MEDIATING ROLE BETWEEN DEPRESSION AND COGNITIVE PERFORMANCE
Xinyu Hao, Fuyang Cao, Ziyao Xu, Shaohua You, Tianyue Mi, Lei Wang, Yongxin Guo, Zhuoning Zhang, Jiangbei Cao, Jingsheng Lou, Yanhong Liu, Xianyang Chen, Zhikang Zhou, Weidong Mi, Li Tong
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BACKGROUND: Recent studies have increasingly emphasized the robust correlation between depression and cognitive function. However, it remains unclear whether this relationship is causal or merely coincidental. To address this uncertainty, we conducted two-sample bidirectional Mendelian randomization (MR) analyses to investigate the connection between depression and cognitive performance.
METHODS: We sourced genome-wide association study (GWAS) data for depression (NSNPs=21,306,230) from the FinnGen (R10) and for cognitive performance (NSNPs=10,049,954) from the IEU GWAS database. Causal effects employed methodologies such as Inverse variance weighted (IVW), weighted median, MR Egger, simple mode and weighted mode. Two-step analysis determined the contribution of the mediator variable to the outcomes. To determine stability and reliability, sensitivity analyses were performed that included an assessment of heterogeneity, horizontal pleiotropy, and the leave-one-out techniques.
RESULTS: This MR analysis identified 8 independent significant SNPs associated with depression and 81 SNPs linked to cognitive performance. Our findings revealed that depression increases the risk of developing deteriorating cognitive performance (IVW β, -0.11; 95 % confidence interval (CI), -0.18 – -0.05; PIVW value= 5.97E-04). Conversely, cognitive performance decline could also predispose individuals to depression [odds ratio (OR)IVW, 0.85; 95 % CI, 0.76 – 0.95; PIVW value=0.004]. Multivariate MR analysis confirmed the robustness of this bidirectional association. A two-step MR mediation analysis indicated that the pathway from depression to cognitive performance is mediated by pain, with a mediation effect size of -0.022 and a mediation ratio of 28.95 %. The pathway from cognitive performance to depression is mediated by frailty, with a mediation effect value of -0.028, representing 22.40 % of the mediation proportion.
CONCLUSION: A two-way causal relationship between depression and cognitive performance, with pain and frailty being mediating factors, respectively. Future research should prioritize mechanistic studies, targeted interventions, and personalized approaches to disentangle and mitigate the bidirectional effects of depression and cognitive performance.
CITATION:
Xinyu Hao ; Fuyang Cao ; Ziyao Xu ; Shaohua You ; Tianyue Mi ; Lei Wang ; Yongxin Guo ; Zhuoning Zhang ; Jiangbei Cao ; Jingsheng Lou ; Yanhong Liu ; Xianyang Chen ; Zhikang Zhou ; Weidong Mi ; Li Tong (2025): Causal relationship and mediating role between depression and cognitive performance. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100196
DRUG DELIVERY STRATEGIES TO CROSS THE BLOOD-BRAIN BARRIER IN ALZHEIMER’S DISEASE: A COMPREHENSIVE REVIEW ON THREE PROMISING STRATEGIES
Lotte A. de Koning, Daniel A. Vazquez-Matias, Wissam Beaino, Daniëlle J. Vugts, Guus A.M.S. van Dongen, Wiesje M. van der Flier, Mario Ries, Dannis G. van Vuurden, Everard G.B. Vijverberg, Elsmarieke van de Giessen
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The field of Alzheimer’s disease (AD) drug development is rapidly changing, with two anti-amyloid monoclonal antibodies (mAbs) having received Food and Drug Administration (FDA) approval, additionally many compounds are in the pipeline. A major obstacle for novel AD therapeutics is the blood-brain barrier (BBB), which restricts passage of particles larger than 400–500 Da. It is estimated that only ∼1 % of mAbs, being ∼150 kDa, passes the BBB, which greatly hampers the efficacy of treatment. To enhance treatment efficacy and to lower the drug dose needed, mechanisms that effectively increase drug delivery across the BBB are urgently sought for. This narrative review describes three promising strategies to enhance drug delivery across the BBB in AD: focused ultrasound (FUS) with microbubbles, receptor-mediated transcytosis (RMT) and delivery using nanoparticle carrier systems. FUS and RMT have shown promising preclinical results and are now being tested in humans whereas nanoparticle carrier systems still need further preclinical validation before clinical application in humans. 89Zr-Immuno-PET provides a unique opportunity to noninvasively monitor and quantitatively assess novel brain delivery methods.
CITATION:
Lotte A. de Koning ; Daniel A. Vazquez-Matias ; Wissam Beaino ; Daniëlle J. Vugts ; Guus A.M.S. van Dongen ; Wiesje M. van der Flier ; Mario Ries ; Dannis G. van Vuurden ; Everard G.B. Vijverberg ; Elsmarieke van de Giessen (2025): Drug delivery strategies to cross the blood-brain barrier in Alzheimer’s disease: a comprehensive review on three promising strategies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100204
VALUE OF BLOOD NEURAL CELL-DERIVED SMALL EXTRACELLULAR VESICLES IN THE DIAGNOSIS AND PREDICTION OF ALZHEIMER\'S DISEASE: A SYSTEMATIC REVIEW
Weibing Pan, Yu Teng, Xiaowan Han, Shaojiao Liu, Xingxue Pang, Lei Wang, Mingjing Zhao
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Blood neural cell-derived small extracellular vesicles (sEVs) can directly reflect changes in brain tissue and are easier to obtain than cerebrospinal fluid. This article systematically reviews the alterations of proteins and miRNAs from neural cell-derived sEVs in patients with Alzheimer's disease (AD), and summarizes the biomarkers with clinical diagnostic and predictive value. PubMed, Web of Science, Embase, and Cochrane Library were searched for studies in blood neural cell-derived sEVs in AD patients up to May 2024. According to the inclusion and exclusion criteria, the literature was screened, the information was extracted and the quality was evaluated. Proteins and miRNAs from neural cell-derived sEVs were classified and summarized, focusing on target molecules with high diagnostic and predictive values for AD. A final 34 articles reporting 5601 participants were included. In cross-sectional studies, Aβ- and Tau-related proteins (Aβ42, Aβ42/40, p-S396-Tau, p-Tau181), p-S312-IRS-1, and cathepsin D were increased, conversely, synaptic proteins (neurogranin, synaptotagmin, synaptophysin, synaptopodin, NMDAR2A) and REST were decreased in blood neuron-derived sEVs (NDsEVs) of patients with AD. While miR-29c-3p was increased in blood NDsEVs and glial cell-derived sEVs. Each of these proteins and miRNAs demonstrated high AD diagnostic value. Additionally, blood astrocyte-derived sEVs (ADsEVs) showed increased complement effector proteins and decreased complement regulatory proteins with a moderate diagnostic value. In longitudinal cohort studies, three composite models displayed high predictive efficacy for early AD prediction, and could predict the occurrence of AD within 1–10 years. Therefore, Aβ- and Tau-related proteins, synaptic proteins, and miRNA in blood neural cell-derived sEVs demonstrate high AD diagnostic and predictive values serving as important biomarkers. Especially, synaptic proteins showed significant changes in the early clinical stage, which has early predictive value.
CITATION:
Weibing Pan ; Yu Teng ; Xiaowan Han ; Shaojiao Liu ; Xingxue Pang ; Lei Wang ; Mingjing Zhao (2025): Reply to the Letter to the Editor: HeValue of blood neural cell-derived small extracellular vesicles in the diagnosis and prediction of Alzheimer's disease: A systematic reviewaring 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.2025.100193
REPLY TO THE LETTER TO THE EDITOR: HEARING LOSS, DIET, AND COGNITIVE DECLINE: INTERCONNECTIONS FOR DEMENTIA PREVENTION
Xiaoran Liu, Uzma S. Akhtar
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CITATION:
Xiaoran Liu ; Uzma S. Akhtar (2025): Reply to the Letter to the Editor: 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.2025.100188
USING MACHINE LEARNING AND ELECTRONIC HEALTH RECORD (EHR) DATA FOR THE EARLY PREDICTION OF ALZHEIMER\'S DISEASE AND RELATED DEMENTIAS
Sonia Akter, Zhandi Liu, Eduardo J. Simoes, Praveen Rao
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BACKGROUND: Over 6 million patients in the United States are affected by Alzheimer's Disease and Related Dementias (ADRD). Early detection of ADRD can significantly improve patient outcomes through timely treatment.
OBJECTIVE: To develop and validate machine learning (ML) models for early ADRD diagnosis and prediction using de-identified EHR data from the University of Missouri (MU) Healthcare.
DESIGN: Retrospective case-control study.
SETTING: The study used de-identified EHR data provided by the MU NextGen Biomedical Informatics, modeled with the PCORnet Common Data Model (CDM).
PARTICIPANTS: An initial cohort of 380,269 patients aged 40 or older with at least two healthcare encounters was narrowed to a final dataset of 4,012 ADRD cases and 119,723 controls.
METHODS: Six ML classifier models: Gradient-Boosted Trees (GBT), Light Gradient-Boosting Machine (LightGBM), Random Forest (RF), eXtreme Gradient-Boosting (XGBoost), Logistic Regression (LR), and Adaptive Boosting (AdaBoost) were evaluated using Area Under the Receiver Operating Characteristic Curve (AUC-ROC), accuracy, sensitivity, specificity, and F1 score. SHAP (SHapley Additive exPlanations) analysis was applied to interpret predictions.
RESULTS: The GBT model achieved the best AUC-ROC scores of 0.809–0.833 across 1- to 5-year prediction windows. SHAP analysis identified depressive disorder, age groups 80–90 yrs and 70–80 yrs, heart disease, anxiety, and the novel risk factors of sleep apnea, and headache.
CONCLUSION: This study underscores the potential of ML models for leveraging EHR data to enable early ADRD prediction, supporting timely interventions, and improving patient outcomes. By identifying both established and novel risk factors, these findings offer new opportunities for personalized screening and management strategies, advancing both clinical and informatics science.
CITATION:
Sonia Akter ; Zhandi Liu ; Eduardo J. Simoes ; Praveen Rao (2025): Using machine learning and electronic health record (EHR) data for the early prediction of Alzheimer's Disease and Related Dementias. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100169
MULTIMORBIDITY AND RISK OF DEMENTIA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF LONGITUDINAL COHORT STUDIES
Yaguan Zhou, Yating You, Yuting Zhang, Yue Zhang, Changzheng Yuan, Xiaolin Xu
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BACKGROUND: Chronic diseases (e.g., hypertension, diabetes, and heart diseases) have been proposed as marked predictors of incident dementia. However, synthesised evidence on the effect of multimorbidity on dementia is still lacking. We aim to summarise the association between multimorbidity and risk of dementia in longitudinal cohorts.
METHODS: In this systematic review and meta-analysis, we conducted a systematic search in PubMed, Web of Science and Embase from inception to Dec 14, 2024, to identify longitudinal cohort studies reporting the association between multimorbidity or multimorbidity patterns and risk of dementia. Information of included studies were extracted by three reviewers (YaZ, YY and YuZ), and the quality assessment was conducted using the Newcastle-Ottawa Scale. The inverse-variance weighted random effects meta-analysis was performed to obtain the pooled hazard ratios (HRs) and 95 % confidence intervals (CIs) for dementia associated with multimorbidity and cardiometabolic multimorbidity (CMM). Cochran's Q test and the I2 statistic were used to indicate heterogeneity among the studies. Meta-regression analysis, subgroup analysis and sensitivity analysis were conducted to determine any valid sources of heterogeneity. This study was registered with PROSPERO (CRD42023403684).
RESULTS: We included 17 longitudinal cohort studies (2262,885 middle-aged and older participants) in the systematic review, of which seven were included in meta-analysis. All studies presented moderate to high methodological quality. Meta-analysis showed a positive association between multimorbidity and incident dementia (HR=1.53, 95 % CI=1.12 to 2.09), with substantial heterogeneity (I2=95.2 %). Studies using health records to measure dementia tend to find a stronger positive relationship between multimorbidity and risk of dementia than those using self-report (HRhealth records=1.94, 95 % CI=1.35 to 2.78, I2=94 %; HRself-report=1.17, 95 % CI=1.07 to 1.28, I2=0 %). The impacts of CMM were also observed, and the HRs for dementia ranged from 2.49 (combination of heart diseases and stroke: 95 % CI=1.64 to 3.78) to 3.77 (combination of diabetes, heart diseases and stroke: 95 % CI=2.02 to 7.02). The heterogeneity was moderate, with I2 ranging from 46.9 % (p for heterogeneity=0.152) to 84.1 % (p for heterogeneity=0.002). The impacts of number of diseases, multimorbidity clusters, and multimorbidity trajectory on risk of dementia were narratively summarised due to lacking comparable studies. Limited evidence (only one study) precluded quantitative synthesis for the association of physical and psychological multimorbidity with dementia.
CONCLUSION: Multimorbidity and CMM pattern were significantly associated with risk of dementia, while the effect of physical and psychological multimorbidity remain inconclusive. Individuals affected by multimorbidity should be prioritised in risk factor modification and dementia prevention. Preventing the development of multimorbidity is also crucial—particularly those who already have one chronic disease—in order to maintain cognitive health.
CITATION:
Yaguan Zhou ; Yating You ; Yuting Zhang ; Yue Zhang ; Changzheng Yuan ; Xiaolin Xu (2025): Multimorbidity and risk of dementia: A systematic review and meta-analysis of longitudinal cohort studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100164
A SIX-YEAR RISK ASSESSMENT FOR DEMENTIA AND ALZHEIMER\'S DISEASE IN THE GENERAL POPULATION THROUGH IMMUNOPRECIPITATION-MASS SPECTROMETRY PLASMA AMYLOID QUANTIFICATION
Germain U. Busto, Christophe Hirtz, Isabelle Carriere, Karim Bennys, Laure-Anne Gutierrez, Jana Kindermans, Catherine Helmer, Audrey Gabelle, Sylvain Lehmann, Claudine Berr
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BACKGROUND: Identifying individuals at risk for dementia and Alzheimer’s disease (AD) in the general population (GP) is increasingly essential due to new diagnostic criteria and opportunities for effective interventions. Plasma-based biomarkers (pBB) offer a promising approach for detecting positive amyloid profile. However, their effectiveness in predicting clinical dementia and AD risk at the GP level remains largely unexplored.
OBJECTIVES: To assess the risk of clinical dementia and AD using pBB amyloid biomarkers in GP using the most up-to-date proteomic techniques.
DESIGN: Case-cohort study randomly selected from a prospective cohort.
SETTING: The three-city community-living study.
PARTICIPANTS: Over 65 years recruited from the electoral rolls of three French cities.
MEASUREMENTS: pBB amyloid levels (Aβ42, Aβ40 and APP669–711) were measured in the plasma using the mass spectrometry-based (IPMS)-Shimadzu modified technology. Patients were monitored for up to 6 years for incident dementia and AD according to DSM-IV and NINCDS/ADRDA criteria. Cox proportional hazard models adjusted for multiple covariables, including age and renal function, were used to estimate hazard ratios.
RESULTS: Plasma samples from 327 participants were analyzed with a mean age 83 years (80–87), 64.8 % females and a median follow-up time of 2.7 years (0.8–4.8) and including 121 incident dementia cases. Our findings indicate that the Aβ42/Aβ40 ratio, along with a composite score that encompasses APP669–711 and Aβ40/Aβ42 ratios, serves as significant predictors of clinical dementia [HR(95 %CI) = 3.52 (1.69–7.32), p-value<0.001 and 4.34 (2.06–9.17), p-value<0.001, respectively] and AD risk over a six-year period, while also accounting for age and sex interactions. Furthermore, elevated Aβ40 levels correlate with an increased risk of developing dementia (HR=2.56, 95 % CI 1.22–5.35, p = 0.01) and AD (HR=2.60, 95 %CI 1.06–6.36, p = 0.04), and our study confirms that Aβ42 concentrations are significantly influenced by renal function.
CONCLUSIONS: This research advances the potential application of plasma amyloid biomarkers for assessing the risk of clinical dementia and AD in the general population within short period of time, positioning it as a valuable tool alongside existing plasma PT217 biomarkers or using ratio of both of them.
CITATION:
Germain U. Busto ; Christophe Hirtz ; Isabelle Carriere ; Karim Bennys ; Laure-Anne Gutierrez ; Jana Kindermans ; Catherine Helmer ; Audrey Gabelle ; Sylvain Lehmann ; Claudine Berr (2025): A six-year risk assessment for dementia and Alzheimer's disease in the general population through immunoprecipitation-mass spectrometry plasma amyloid quantification. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100186
ASSOCIATION OF THE DIFFERENCE BETWEEN CYSTATIN C- AND CREATININE-BASED ESTIMATED GLOMERULAR FILTRATION RATE WITH CEREBRAL SMALL VESSEL DISEASE: A LARGE PROSPECTIVE COHORT STUDY
Zhiming Li, Fei Wang, Jincheng Liu, Benbo Xiong, Han Wang, Zijie Wang, Xiao Hu, Qi Li
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BACKGROUND AND OBJECTIVE: It remains unclear whether the difference between the estimated glomerular filtration rate based on cystatin C and creatinine (eGFRdiff) is associated with cerebral small vessel disease (CSVD). We investigated the correlation of eGFRdiff with SCVD and further evaluated the mediating role of blood pressure.
METHODS: This prospective cohort study included 35,590 neurologically healthy participants at baseline (2006 to 2010) from the UK Biobank. eGFRdiff is divided into two indicators: absolute difference (eGFRabdiff) and ratio (eGFRrediff) based on the calculation between cystatin C and creatinine. CSVD was assessed by calculating white matter hyperintensity volume (WMHV) from T2-FLAIR brain MRI scans (conducted between 2014 and 2021), with values normalized to intracranial volume and log-transformed. Multiple linear regression models and mediation analysis was used to evaluate the associations of eGFRdiff with WMHV.
RESULTS: Participants with negative eGFRabdiff had higher WMHV (β = 0.07, 95 % confidence interval [CL] = 0.04 ∼ 0.10), while participants with positive eGFRabdiff had smaller WMHV (β = -0.05, 95 %CL = -0.09 ∼ -0.02), compared to midrange eGFRabdiff group. Meanwhile, participants with eGFRrediff ≤ 0.7 had higher WMHV compared with participants with eGFRrediff > 0.7 (β = 0.08, 95 %CL = 0.01∼ 0.15) .In addition, hypertension mediated the associations between eGFRdiff and WMHV (12.6 % ∼13.2 %).
CONCLUSION: eGFRdiff was independently associated with WMHV. Our findings suggested that monitoring eGFRdiff has potential benefits in identifying the burden of CSVD in the general population in future.
CITATION:
Zhiming Li ; Fei Wang ; Jincheng Liu ; Benbo Xiong ; Han Wang ; Zijie Wang ; Xiao Hu ; Qi Li (2025): Association of the difference between cystatin C- and creatinine-based estimated glomerular filtration rate with cerebral small vessel disease: A large prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100190
BRAIN PHOTOBIOMODULATION: A POTENTIAL TREATMENT IN ALZHEIMER’S AND PARKINSON’S DISEASES
Guillaume Blivet, Benjamin Touchon, Hugo Cavadore, Sara Guillemin, Frédéric Pain, Michael Weiner, Marwan Sabbagh, Cécile Moro, Jacques Touchon
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Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) are common neurodegenerative diseases, characterized by the progressive loss of synapses and neurons, leading to cognitive and motor decline. Their pathophysiology includes cerebral lesions, oxidative stress, neuroinflammation as well as brain-gut axis microbiota dysbiosis.
Preclinical investigations demonstrated that brain photobiomodulation (bPBM) reduces oxidative stress and inflammation, increases cerebral blood flow and enhance neurogenesis and synaptogenesis, which makes bPBM a promising treatment in AD and PD.
This review focuses on the clinical application of bPBM in AD and PD. It aims to provide a scientific overview of the current clinical knowledge, review recent clinical studies findings, and describe future directions and upcoming clinical studies.
So far, several clinical studies investigated bPBM therapy, at various parameters, both in patients with AD and related dementia, and PD. All demonstrate bPBM safety and bring valuable clinical information regarding efficacy, with particularly promising results in AD. However, their exploratory design and inconsistent quality lead to a low level of evidence, which currently does not support the widespread use of bPBM in clinical practice.
Future clinical research should address two gaps: the need for robust double-blinded RCTs vs sham with a higher number of patients and a longer follow-up, and the need for research focusing on dosimetry to determine which bPBM parameters are optimal. The ongoing or unpublished clinical studies on bPBM should fill in this gap.
CITATION:
Guillaume Blivet ; Benjamin Touchon ; Hugo Cavadore ; Sara Guillemin ; Frédéric Pain ; Michael Weiner ; Marwan Sabbagh ; Cécile Moro ; Jacques Touchon (2025): Brain photobiomodulation: a potential treatment in Alzheimer’s and Parkinson’s diseases. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100185
POOR GLYMPHATIC FUNCTION IS ASSOCIATED WITH MILD COGNITIVE IMPAIRMENT AND ITS PROGRESSION TO ALZHEIMER\'S DISEASE: A DTI-ALPS STUDY
Cuiping Bao, Hongbin Luo, Jiao Wang, Xuehuan Liu, Yiming Li, Jun Yang, Chong Chen, Rongrong Yang, Weili Ba, Xinying Lian, Michelle Dunk, Jun Liu, Weili Xu
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BACKGROUND: We aimed to explore the association between ALPS index and both risks of MCI from cognitively normal (CN) and incident AD progressed from MCI, as well as potential mediating factors.
METHODS: This study included 519 adults including 253 (48.75 %) CN and 266 (51.25 %) MCI participants from Alzheimer's Disease Neuroimaging Initiative. Glymphatic function (assessed by along the perivascular space [ALPS] index) was measured by diffusion tensor image at baseline. Neurobiomarkers (Aβ and tau from CSF, plasma and PET) and cognitive functions were served as mediators. Data were analyzed using Cox and Laplace regression and mediation analysis.
RESULTS: During follow-up (median 3.6 years, interquartile range [IQR]: 2.0–4.9 years), 30 (11.86 %) participants developed MCI in the CN cohort and 73 (27.4 %) participants progressed to AD in the MCI cohort. The hazard ratios (95 % confidence intervals [CIs]) of the higher ALPS index was 0.605 (0.386–0.948) for MCI and 0.501 (0.356–0.706) for AD. In addition, participants with high ALPS index had 3.837 and 3.466 years prolonged onset of MCI and AD, separately. Aβ in choroid plexus (17.1 %), tau in cortex [Inferiortemporal (21.1 %), Middletemporal (AV1451:17.0 %, FTP:15.5 %), Superiortemporal(7.7 %), Meta_temporal (AV1451:17.5 %, FTP:16.6 %)], and executive function (14.1 %) mediated the association between ALPS and MCI-AD progression.
CONCLUSION: High ALPS index decreases MCI risk and delays MCI progression to AD by approximately 3.5 years. Aβ in choroid plexus, tau in cortex, and executive function may partially mediate the MCI-AD progression in relation to ALPS index.
CITATION:
Cuiping Bao ; Hongbin Luo ; Jiao Wang ; Xuehuan Liu ; Yiming Li ; Jun Yang ; Chong Chen ; Rongrong Yang ; Weili Ba ; Xinying Lian ; Michelle Dunk ; Jun Liu ; Weili Xu (2025): Poor glymphatic function is associated with mild cognitive impairment and its progression to Alzheimer's disease: A DTI-ALPS study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100156
FINGOLIMOD AMELIORATES AMYLOID DEPOSITION AND NEURODEGENERATION IN APP/PS1 MOUSE MODEL OF ALZHEIMER\'S DISEASE
Meng-Ting Wang, Zi-Cheng Hu, Yang Xiang, Xiao-Qin Zeng, Zhang-Cheng Fei, Jia Chen, Xin-Peng Li, Yu-Peng Zhu, Jun Wang, Yan-Jiang Wang, Zhi-Qiang Xu, Yu-Hui Liu
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INTRODUCTION: The immune system plays a critical role in regulating amyloid-beta (Aβ) metabolism in Alzheimer's Disease (AD). Both T and B lymphocytes are involved in the pathogenesis of AD. The sphingosine-1-phosphate (S1P) receptor modulator fingolimod used in the treatment of multiple sclerosis, can promote lymphocyte homing, potentially reducing the infiltration of peripheral lymphocytes into the brain.
METHODS: In this study, 8-month-old APP/PS1 mice were orally administered fingolimod at a dose of 1 mg/kg/day or saline as a control for 2 months. After treatment, the mice were subjected to behavioral tests, pathological examinations, and biochemical analyses to evaluate behavioral deficits and AD-type pathologies.
RESULTS: Fingolimod inhibits the infiltration of peripheral lymphocytes into the brain and reduces neuroinflammation. Fingolimod enhances cognitive function and alleviates brain Aβ deposition. Additionally, fingolimod treatment mitigates other AD-related pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Proteomic analysis further confirms the therapeutic effects of fingolimod in AD, reflected by the downregulation of proteins involved in multiple AD-associated pathways.
DiISCUSSION: This study illustrates that fingolimod effectively ameliorates multiple pathological features of AD, highlighting its potential as a promising therapeutic candidate for the disease.
CITATION:
Meng-Ting Wang ; Zi-Cheng Hu ; Yang Xiang ; Xiao-Qin Zeng ; Zhang-Cheng Fei ; Jia Chen ; Xin-Peng Li ; Yu-Peng Zhu ; Jun Wang ; Yan-Jiang Wang ; Zhi-Qiang Xu ; Yu-Hui Liu (2025): Fingolimod ameliorates amyloid deposition and neurodegeneration in APP/PS1 mouse model of Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100131
PHENOTYPIC ALTERATIONS IN PERIPHERAL BLOOD B LYMPHOCYTES OF PATIENTS WITH ALZHEIMER\'S DISEASE
Meng-Ting Wang, Ye-Ran Wang, Gui-Hua Zeng, Xiao-Qin Zeng, Zhang-Cheng Fei, Jia Chen, Jin Zhou, Xin-Peng Li, Zhi-Qiang Xu, Yan-Jiang Wang, Yu-Hui Liu
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INTRODUCTION: Dysfunction of humoral immunity has been implicated in the pathogenesis of Alzheimer's disease (AD). The distribution of B lymphocyte subsets and their clinical relevance in AD remain unclear.
OBJECTIVE: In this study, we aimed to investigate the distribution of peripheral blood B lymphocyte subsets and their relevance with cognition and biomarkers in AD.
DESIGN, SETTING, AND PARTICIPANTS: We evaluated the immunophenotype of peripheral B lymphocytes in 27 AD patients confirmed by PET-Amyloid scan and 32 cognitively normal controls.
RESULTS: The phenotype of B lymphocytes is altered in AD patients. AD patients exhibit a decrease in both the numbers and proportions of switched memory (SwM) B cells and double-negative (DN) B cells. The proportion of unswitched memory (USwM) B cells was increased after in vitro stimulation. Additionally, B cells that produce proinflammatory cytokines including GM-CSF, IFN-γ, and TNF-α are increased, while those that produce the anti-inflammatory cytokine IL-10 are decreased in AD patients after in vitro stimulation. These alterations in B cell populations were linked to cognitive functions and biomarkers, including Aβ42/40 and pTau181, in AD patients.
DISCUSSION: This study reveals an altered B-lymphocyte phenotype in AD patients, marked by functional and compositional dysregulation. Further research incorporating mechanistic, longitudinal, and functional studies is needed to determine whether these immune perturbations directly contribute to AD pathogenesis or arise as secondary effects of neurodegeneration.
CITATION:
Meng-Ting Wang ; Ye-Ran Wang ; Gui-Hua Zeng ; Xiao-Qin Zeng ; Zhang-Cheng Fei ; Jia Chen ; Jin Zhou ; Xin-Peng Li ; Zhi-Qiang Xu ; Yan-Jiang Wang ; Yu-Hui Liu (2025): Phenotypic alterations in peripheral blood B Lymphocytes of patients with Alzheimer's Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100135
JPAD Volume 12, N°06 - 2025
EDITORIAL: NOT A SLAM DUNK (OR FREE LUNCH): THE COMPLEX FUTURE OF ALZHEIMER\'S COMBINATION THERAPY
Cristina Sampaio
J Prev Alz Dis 2025;6(12)
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CITATION:
Cristina Sampaio (2025): Editorial: Not a slam dunk (or Free Lunch): The complex future of Alzheimer's combination therapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100211
EDITORIAL: HERPES ZOSTER AND DEMENTIA : MORE EVIDENCES FOR A CAUSAL LINK
Jean-François Dartigues, Morgane Linard
J Prev Alz Dis 2025;6(12)
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CITATION:
Jean-François Dartigues ; Morgane Linard (2025): Editorial: Herpes zoster and dementia : more evidences for a causal link. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100201
EDITORIAL: PREVENTING ALZHEIMER\'S DISEASE BY CORRECTING LIFESTYLE FACTORS?
Natalio Vita
J Prev Alz Dis 2025;6(12)
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CITATION:
Natalio Vita (2025): Editorial: Preventing Alzheimer's disease by correcting lifestyle factors?. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100212
EDITORIAL: BRAIN HEALTH PRO/SANTE CERVEAU PRO: THE DEVELOPMENT OF A WEB-BASED PROGRAM FOR DEMENTIA LITERACY AND RISK FACTOR REDUCTION
Alex Bahar-Fuchs
J Prev Alz Dis 2025;6(12)
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CITATION:
Alex Bahar-Fuchs (2025): Editorial: Brain health PRO/santé cerveau PRO: The development of a web-based program for dementia literacy and risk factor reduction. The Journal of Prevention of Alzheimer’s Disease (JPAD).
CITATION:
Alex Bahar-Fuchs (2025): Editorial: Brain health PRO/santé cerveau PRO: The development of a web-based program for dementia literacy and risk factor reduction. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
CHALLENGES AND OPPORTUNITIES FOR NOVEL COMBINATION THERAPIES IN ALZHEIMER\'S DISEASE: A REPORT FROM THE EU/US CTAD TASK FORCE
D. Angioni, L. Middleton, R. Bateman, P. Aisen, A. Boxer, S. Sha, J. Zhou, I. Gerlach, R. Raman, H. Fillit, S. Salloway, R. Sperling, B. Vellas, J. Cummings
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryFollowing the recent approvals of anti-amyloid immunotherapies as “first-in-kind” disease-modifying agents for Alzheimer's disease (AD), there is an emerging emphasis in combination therapies, given the complex and multifactorial etiopathogenesis and pathophysiology of the disease. The EU/US CTAD Task Force met in Madrid in October 2024, to discuss biological rationale and methodological issues and outline potential directions for future research in combination therapies. The Task Force agreed on the necessity and urgency of advancing combination therapies for AD treatment. As of January 1, 2024, in the drug development pipeline, there were 21 combination trials (13 % of all trials). The combination of anti-amyloid and anti-tau therapies could become a central focus of the field. Combinations involving anti-inflammatory and immune mechanisms with anti-amyloid or other therapies also have promise. To facilitate the development and implementation of combination therapies, collaborations between sponsors and public-private partnerships are essential. Optimizing the likelihood of success primarily requires leveraging the use of biomarkers and a clearer understanding of the biological mechanisms underpinning AD and their interactions, especially those involving amyloid, tau, and inflammation, that lead to cognitive decline and progression.
CITATION:
D. Angioni ; L. Middleton ; R. Bateman ; P. Aisen ; A. Boxer ; S. Sha ; J. Zhou ; I. Gerlach ; R. Raman ; H. Fillit ; S. Salloway ; R. Sperling ; B. Vellas ; J. Cummings (2025): Challenges and opportunities for novel combination therapies in Alzheimer's disease: a report from the EU/US CTAD Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100163
HERPES ZOSTER AS RISK FACTOR FOR DEMENTIA: A MATCHED COHORT STUDY OVER 20 YEARS IN A 10-MILLION POPULATION IN ITALY
Lorenzo Blandi, Paola Bertuccio, Carlo Signorelli, Helmut Brand, Timo Clemens, Cristina Renzi, Anna Odone
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Herpes Zoster is caused by the reactivation of the Varicella-Zoster Virus. Zoster may influence the occurrence of dementia, but contradictory results about this association emerged from recent studies. These findings did not consider the severity of Zoster and observed individuals for limited follow-up time. Our study used a region-wide Italian registry to investigate the association between severe Zoster infection and dementia occurrence over a 23-year period.
METHODS: We included people aged ≥ 50 and hospitalised with Zoster, and two comparison cohorts from both the general population and the hospitalised population without Zoster. By random sampling, the matching 1:5 was based on sex, birth year, and entry date in the cohort. Dementia and Zoster were identified through validated algorithms. A Fine-Gray sub-distribution hazard model was used, accounting for competing risk of death.
RESULTS: We identified 132,968 individuals, of whom 12,088 with severe Zoster, 60,440 matched controls among the general population, and 60,440 matched controls among the hospitalised population. In severe cases of Herpes Zoster, the overall adjusted sub-distributed hazard ratio of dementia was 1.13 (95 % CI 1.07–1.19) compared to the general population, and 1.08 (95 % CI 1.03–1.14) compared to hospitalised population. Hazard ratios were still significant in different strata group, including by sex, age group (including in 50–65 younger adults) and at different follow-up period.
CONCLUSIONS: Our population-based study found an increased risk of developing dementia among severe Zoster cases. Those results support the importance of improving Zoster prevention and extending the vaccination recommendations to younger age groups.
CITATION:
Lorenzo Blandi ; Paola Bertuccio ; Carlo Signorelli ; Helmut Brand ; Timo Clemens ; Cristina Renzi ; Anna Odone (2025): Herpes zoster as risk factor for dementia: a matched cohort study over 20 years in a 10-million population in Italy. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100167
LIFESTYLE FACTORS AND PLASMA BIOMARKERS OF ALZHEIMER\'S DISEASE: A NARRATIVE REVIEW
Claudie Hooper, Nicola Coley, Julien Delrieu, Sophie Guyonnet
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryAlzheimer's disease (AD) is a neurodegenerative disorder characterised by amyloid-β (Aβ), tau hyperphosphorylation and neurodegeneration. Blood-based biomarkers are emerging as a minimally invasive tool for disease detection and monitoring. This review depicts the relationships between modifiable lifestyle factors (nutrition, physical activity (PA), sleep, alcohol consumption, smoking, and social isolation) and plasma biomarkers of AD: Aβ42, Aβ40, Aβ42/40, phosphorylated tau, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein. Limited evidence suggests that better nutrition is associated with favourable AD plasma biomarker profiles and that PA is associated with less plasma NfL and Aβ, whilst poor sleep is associated with elevated plasma Aβ. However, lack of data and inconsistent findings highlight the need for further investigation to substantiate or refute these trends. Moreover, future research should include the analysis of lifestyle on plasma biomarkers according to gender, metabolic health and APOE status. Considering the growing emphasis on modifiable lifestyle factors for preventing and delaying dementia onset further investigation is justified.
CITATION:
Claudie Hooper ; Nicola Coley ; Julien Delrieu ; Sophie Guyonnet (2025): Lifestyle factors and plasma biomarkers of Alzheimer's disease: A narrative review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100130
BRAIN HEALTH PRO/SANTE CERVEAU PRO: THE DEVELOPMENT OF A WEB-BASED PROGRAM FOR DEMENTIA LITERACY AND RISK FACTOR REDUCTION
Sylvie Belleville, Nicole D. Anderson, Louis Bherer, Richard Camicioli, Julie Carrier, Senny Chan, Marc Cuesta, Thien Thanh Dang-Vu, Emily Dwosh, Alexandra J. Fiocco, Guylaine Ferland, Brigitte Gilbert, Elaine Harris, Inbal Itzhak, Pamela Jarrett, Mohamed Abdelhafid Kadri, Danielle Laurin, Teresa Liu-Ambrose, Chris A. McGibbon, Laura Middleton, Lesley Miller, Haakon B. Nygaard, Manuel Montero-Odasso, Kelly Murphy, Natalie Phillips, M. Kathleen Pichora-Fuller, Julie M. Robillard, Eric E. Smith, Mark Speechley, Amal Trigui, Walter Wittich, Howard Chertkow, Howard H. Feldman
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Online educational programs focused on ways to improve brain health could increase participant literacy, empowerment, and engagement in activities that support personal brain health, potentially reducing dementia risk.
OBJECTIVES: Our goal was to develop an evidence-based online educational program with a focus on risk and protective factors for dementia. Here we present the rationale and features of the program and include results from a pilot study that assessed usability and acceptability.
DESIGN: This project is part of the Can-Thumbs UP (CTU) initiative. An Intervention Mapping Approach framework and co-construction approach was used to develop the online program. A pre-post pilot open label design was used to test the usability and acceptance of this at-home educational program.
SETTING: The program and assessment for the pilot study were delivered fully remotely.
PARTICIPANTS: Twenty community-dwelling older adults (60–83 years of age, 65 % female) living in Canada who were at increased risk of dementia.
PROGRAM: The Brain Health PRO/Santé Cerveau PRO is a web-based 45-week program available in French and English. It provides general information and guidance on seven modifiable risk factors for dementia: physical activity, nutrition, cognitively stimulating activities, sleep, social and psychological health, vascular health, and vision/hearing. After completing a brief intake questionnaire, users are provided with an individualized risk profile to personalize priorities and goals. During the course of the program, users receive feedback on lifestyle changes. For this pilot study, participants completed a 15-week version of the program.
MEASUREMENTS: This pilot study reports measures of usability (System Usability Scale), acceptance (Technology Acceptance Model-2) as well as risk profiles at intake based on self-reported questionnaires.
RESULTS: Two logic models were developed to identify the determinants of risk for dementia and how these could be targeted by the program. A review of dementia risk and protective factors and online educational programs for older adults, as well as co-creation activities with experts, stakeholders, and citizen advisors, were used to identify the determinants, target, format, and content of the program. The pilot study reports excellent usability and acceptance with scores of 80.4/100 and 93.5/120 respectively.
CONCLUSION: Intervention mapping and co-construction approaches facilitated the design of a program that effectively balances the delivery of scientific content with the specific constraints, needs and abilities of older adults.
CITATION:
Sylvie Belleville ; Nicole D. Anderson ; Louis Bherer ; Richard Camicioli ; Julie Carrier ; Senny Chan ; Marc Cuesta ; Thien Thanh Dang-Vu ; Emily Dwosh ; Alexandra J. Fiocco ; Guylaine Ferland ; Brigitte Gilbert ; Elaine Harris ; Inbal Itzhak ; Pamela Jarrett ; Mohamed Abdelhafid Kadri ; Danielle Laurin ; Teresa Liu-Ambrose ; Chris A. McGibbon ; Laura Middleton ; Lesley Miller ; Haakon B. Nygaard ; Manuel Montero-Odasso ; Kelly Murphy ; Natalie Phillips ; M. Kathleen Pichora-Fuller ; Julie M. Robillard ; Eric E. Smith ; Mark Speechley ; Amal Trigui ; Walter Wittich ; Howard Chertkow ; Howard H. Feldman ; the CTU expert group for the Canadian Consortium on Neurodegeneration in Aging (CCNA), CAN-THUMBS UP Study Group (2025): Brain health PRO/Santé cerveau PRO: The development of a web-based program for dementia literacy and risk factor reduction. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100134
SAMPLE SIZE ESTIMATES FOR BIOMARKER-BASED OUTCOME MEASURES IN CLINICAL TRIALS IN AUTOSOMAL DOMINANT ALZHEIMER\'S DISEASE
David M Cash, Katy E Morgan, Antoinette O\'Connor, Thomas D Veale, Ian B Malone, Teresa Poole, Tammie LS Benzinger, Brian A Gordon, Laura Ibanez, Yan Li, Jorge J. Llibre-Guerra, Eric McDade, Guoqiao Wang, Jasmeer P Chhatwal, Gregory S Day, Edward Huey, Mathias Jucker, Johannes Levin, Yoshiki Niimi, James M Noble, Jee Hoon Roh, Racquel Sánchez-Valle, Peter R Schofield, Randall J Bateman, Chris Frost, Nick C Fox, The Dominantly Inherited Alzheimer Network (DIAN)
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryINTRODUCTION: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.
METHODS: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).
RESULTS: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).
DISCUSSION: Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.
CITATION:
David M Cash ; Katy E Morgan ; Antoinette O'Connor ; Thomas D Veale ; Ian B Malone ; Teresa Poole ; Tammie LS Benzinger ; Brian A Gordon ; Laura Ibanez ; Yan Li ; Jorge J. Llibre-Guerra ; Eric McDade ; Guoqiao Wang ; Jasmeer P Chhatwal ; Gregory S Day ; Edward Huey ; Mathias Jucker ; Johannes Levin ; Yoshiki Niimi ; James M Noble ; Jee Hoon Roh ; Racquel Sánchez-Valle ; Peter R Schofield ; Randall J Bateman ; Chris Frost ; Nick C Fox ; The Dominantly Inherited Alzheimer Network (DIAN) (2025): Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100133
A SYSTEMATIC REVIEW OF TARGETED DEMENTIA RISK REDUCTION INTERVENTIONS IN MIDDLE-AGED ADULTS IN PRIMARY CARE
Mary Tullipan, Johnson George, Parker Magin, Kali Godbee, Jane Ferns, Claire Frewin
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Pathological changes of dementia are thought to commence in mid-life, making mid-life an attractive target for dementia risk reduction. This review assessed the current literature on multidomain dementia risk-reduction interventions in mid-life.
METHODS: We systematically searched MEDLINE, CINAHL and EMBASE for eligible studies. Studies were included if (i) participants had a mean age between 45 and 65 years, (ii) the intervention was delivered in a primary care setting and targeted two or more dementia risk factors, and (iii) outcomes were change in cognitive function or change in risk score. Data was extracted and assessed for bias using the revised Cochrane risk-of-bias assessment tool.
RESULTS: Seven studies were included. Participants' mean age ranged from 45.3 to 64.2 years. Interventions ranged from 10 weeks to 9.8 years and targeted between two and six dementia risk factors. There was a large variation in the type of outcome and statistical tests utilised across the included studies, impacting the ability to draw comparisons between the studies and draw conclusions regarding treatment effects. There was a high risk of bias in three of the studies and some concerns of bias in the other four studies. Two studies assessing dementia risk found a reduction in risk scores at their primary endpoint. None of the included studies found a statistically significant change in cognition from their interventions. This may be attributable in part to not assessing cognition prior to the interventions, limited risk factors being addressed, and the short follow-up/duration of the studies.
CONCLUSION: Current evidence for multidomain dementia risk-reduction interventions in mid-life is not definitive; however, given their substantive potential benefits and likely limited harms, they may be considered for implementation in clinical practice after further evaluation. Future trials that have longer follow-ups, target a broader range of dementia risk factors, and that use consistent outcome measures will be valuable. Strategies to maximise implementation of multidomain interventions and long-term effectiveness will enhance the evidence base for dementia prevention in primary care.
CITATION:
Mary Tullipan ; Johnson George ; Parker Magin ; Kali Godbee ; Jane Ferns ; Claire Frewin (2025): A systematic review of targeted dementia risk reduction interventions in middle-aged adults in Primary Care. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100187
DIETARY PATTERNS AND BLOOD-BASED BIOMARKERS OF ALZHEIMER\'S DISEASE IN COGNITIVELY INTACT OLDER ADULTS: FINDINGS FROM A POPULATION-BASED STUDY
Anja Mrhar, Adrián Carballo-Casla, Giulia Grande, Martina Valletta, Claudia Fredolini, Laura Fratiglioni, Milica Gregori? Kramberger, Aleš Kuhar, Bengt Winblad, Amaia Calderón-Larrañaga, Davide Liborio Vetrano
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Diet can impact cognitive aging, but comprehensive data from human studies is lacking and the underlying biological mechanisms are still not fully understood.
OBJECTIVES: To investigate the associations between two dietary patterns consistently linked to inflammation and brain health [the Mediterranean diet (MDS) and inflammatory potential of diet (EDII)] and five blood-based biomarkers of Alzheimer´s disease (AD) in a sample of dementia-free community-dwelling older adults.
DESIGN AND SETTING: We used cross-sectional data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K).
PARTICIPANTS: Participants who were institutionalized, had dementia or Parkinson's disease, or had missing data on diet and/or biomarkers were excluded. Our study sample consisted of 1907 adults ≥60 years old.
MEASUREMENTS: Adherence to the MDS and EDII was assessed using a validated food frequency questionnaire. T-tau, p-tau181, Aβ 42/40, NfL, and GFAP were measured in serum. Associations were estimated through quantile regression models at the 25th, 50th, and 75th percentiles of the biomarkers’ levels, and were adjusted for potential confounders and stratified by sex, age, and APOE-e4 genotype.
RESULTS: In the whole sample, higher adherence to the MDS was associated with lower levels of p-tau181 at the 50th and 75th percentiles [β (95% CI) per 1-SD increment = -0.028 (-0.053, -0.002) and -0.036 (-0.072, -0.001), respectively], while higher adherence to the EDII was associated with higher levels of NfL at the 75th percentile [β (95% CI) per 1-SD increment =0.031 (0.008, 0.053)]. Associations with other biomarkers were only apparent at lower levels of their distribution. Subgroup analyses showed: 1) a stronger inverse association between the MDS and p-tau181 in APOE-e4 carriers than non-carriers, and 2) an inverse association of the MDS with GFAP only in participants ≥78 years.
CONCLUSIONS: Diet seems to be associated with biomarkers of AD pathology in cognitively intact older adults. Some associations were more apparent in the presence of genetic predisposition for AD or advanced age.
CITATION:
Anja Mrhar ; Adrián Carballo-Casla ; Giulia Grande ; Martina Valletta ; Claudia Fredolini ; Laura Fratiglioni ; Milica Gregorič Kramberger ; Aleš Kuhar ; Bengt Winblad ; Amaia Calderón-Larrañaga ; Davide Liborio Vetrano (2025): Dietary patterns and blood-based biomarkers of Alzheimer's disease in cognitively intact older adults: Findings from a population-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100124
BASELINE HABITUAL DIETARY NITRATE INTAKE AND ALZHEIMER\'S DISEASE RELATED NEUROIMAGING BIOMARKERS IN THE AUSTRALIAN IMAGING, BIOMARKERS AND LIFESTYLE STUDY OF AGEING
Anjana Rajendra, Nicola P. Bondonno, Kevin Murray, Liezhou Zhong, Stephanie R. Rainey-Smith, Samantha L. Gardener, Lauren C. Blekkenhorst, Vincent Doré, Victor L. Villemagne, Simon M. Laws, Belinda M. Brown, Kevin Taddei, Colin L. Masters, Christopher C. Rowe, Christopher C. Rowe, Jonathan M. Hodgson, Catherine P. Bondonno, AIBL Research Group
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Dietary nitrate, as a nitric oxide (NO) precursor, may support brain health and protect against dementia.
OBJECTIVE: Our primary aim was to investigate whether dietary nitrate is associated with neuroimaging markers of brain health linked with Alzheimer's disease (AD).
PARTICIPANTS: Study participants were cognitively unimpaired individuals from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) who had β-amyloid positron emission tomography (PET) scans (n = 554) and magnetic resonance imaging (MRI) scans (n = 335) and had completed a Food Frequency Questionnaire at baseline.
METHODS: Source-specific nitrate intakes were estimated using comprehensive nitrate food composition databases. Rates of cerebral β-amyloid (Aβ) deposition, measured using PET, and rates of brain atrophy, measured using MRI, were assessed between baseline and 126-months follow-up, at intervals of 18 months. Multivariable-adjusted linear mixed effect models were used to examine associations between baseline source-specific nitrate intake and rates of (i) cerebral Aβ deposition and (ii) brain atrophy, over the 126 months of follow-up. Analyses were carried out following stratification of the sample by established dementia Alzheimer's disease (AD) risk factors including sex and presence or absence of the apolipoprotein E (APOE) ε4 allele.
RESULTS: In women carriers of the APOE ε4 allele, higher plant sourced nitrate intake (median intake 121 mg/day), was associated with a slower rate of cerebral Aβ deposition [β: 4.47 versus 8.99 Centiloid (CL) /18 months, p < 0.05] and right hippocampal atrophy [-0.01 versus -0.03 mm3 /18 months, p < 0.01], after multivariable adjustments. Moderate intake showed protective associations in men carriers and in both men and women non-carriers of APOE ε4.
CONCLUSIONS: Associations were observed between plant-derived nitrate intake and cerebral Aβ deposition, particularly in high-risk populations (women and APOE ε4 carriers). Associations were also observed for brain volume atrophy, however these exhibited subgroup variability without clear patterns relative to sex and APOE ε4 allele carriage. These findings suggest a potential link between plant-sourced nitrate and AD related neuroimaging markers of brain health improved brain health, but further validation in larger studies is required.
CITATION:
Anjana Rajendra ; Nicola P. Bondonno ; Kevin Murray ; Liezhou Zhong ; Stephanie R. Rainey-Smith ; Samantha L. Gardener ; Lauren C. Blekkenhorst ; Vincent Doré ; Victor L. Villemagne ; Simon M. Laws ; Belinda M. Brown ; Kevin Taddei ; Colin L. Masters ; Christopher C. Rowe ; Ralph N Martins ; Jonathan M. Hodgson ; Catherine P. Bondonno ; AIBL Research Group (2025): Baseline habitual dietary nitrate intake and Alzheimer's Disease related neuroimaging biomarkers in the Australian Imaging, Biomarkers and Lifestyle study of ageing. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100161
LIFESTYLE AND COGNITION: SEPARATING THE EFFECTS OF AVERAGE LIFESTYLE AND LIFESTYLE CHANGES BASED ON THE LIBRA SCORE
KEJ Wesenhagen, K Deckers, HSJ Picavet, ML Rietman, AAL Kok, S Köhler, MA Ikram, FJ Wolters, M Huisman, WMM Verschuren
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: The LIfestyle for BRAin Health (LIBRA) score, consisting of twelve factors, highlights individuals’ potential for dementia risk reduction through lifestyle. The LIBRA score includes modifiable protective factors such as low to moderate alcohol consumption, and risk factors such as hypertension.
OBJECTIVE: We studied whether LIBRA scores are longitudinally associated with cognition, and to what extent this is due to between-person differences or within-person changes in LIBRA scores.
METHODS: Individuals were included from four Dutch community-based cohorts: Doetinchem Cohort Study (DCS; n = 4770), Maastricht Aging Study (MAAS; n = 1295), Longitudinal Aging Study Amsterdam (LASA; n = 2391) and the Rotterdam Study (RS; n = 5205). The number of available LIBRA components (range 7–11) and timepoints (range 3–9) differed per cohort. Outcomes were standardized processing speed (LDST), memory (15-word delayed recall of the verbal learning test (VLT)) and verbal fluency. Hybrid mixed models were fit for the association of 1) mean LIBRA score and 2) change in LIBRA between subsequent timepoints. Models were adjusted for age, sex, education and learning effects. Interactions of the mean LIBRA score with age, and change in LIBRA score with age were tested in two separate models.
RESULTS: Higher (i.e., unhealthier) mean LIBRA scores were associated with worse cognitive speed (lower LDST z-score per 1-point higher LIBRA, range between cohorts: 0.039 – 0.0587), memory (VLT, 0.026 – 0.035), and fluency (0.020 – 0.033). Associations of mean LIBRA scores with cognitive function were stronger with older age (LDST: significant age-interaction, 2 out of 4 cohorts; VLT and fluency: 1 out of 4 cohorts). Relative to 65-year-old individuals with a mean LIBRA score at the 50th percentile, individuals at the 90th percentile of the LIBRA score showed an estimated 1.9–3.2 years more advanced cognitive ageing for LDST, 1.9 – 5.3 years for VLT and 1.4 – 1.7 years for fluency. Within-person change in LIBRA showed no consistent associations with cognitive decline.
CONCLUSIONS: An individual's mean LIBRA score, but not their change in LIBRA score over time, was longitudinally associated with cognitive functioning. In the general population, the investigated version of the LIBRA score is possibly not suitable to capture how cognition (as a proxy for dementia risk) changes with improvements in lifestyle.
CITATION:
KEJ Wesenhagen ; K Deckers ; HSJ Picavet ; ML Rietman ; AAL Kok ; S Köhler ; MA Ikram ; FJ Wolters ; M Huisman ; WMM Verschuren (2025): Lifestyle and cognition: Separating the effects of average lifestyle and lifestyle changes based on the LIBRA score. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100159
ASSOCIATIONS BETWEEN THE EAT-LANCET PLANETARY HEALTH DIET AND INCIDENT DEMENTIA
Jessica Samuelsson, Isabelle Glans, Anna Stubbendorff, Ulrika Ericson, Sebastian Palmqvist, Oskar Hansson, Emily Sonestedt
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: The impact of the environmentally sustainable EAT-Lancet diet on dementia risk remains poorly understood. The aim was to investigate associations between the EAT-Lancet diet and incident dementia.
METHODS: Associations of the EAT-Lancet diet with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were investigated among 25,898 participants from the Malmö Diet and Cancer study, Sweden. Participants aged 45–73 years were recruited for the baseline examination between 1991 and 1996, and the mean follow-up time was 18 years. To assess robustness of estimations, we used seven previously constructed EAT-Lancet diet scores. Multi-adjusted Cox proportional hazard analyses were performed, with results presented per 10 % in increment scores. Additionally, we explored the potentially modifying effect of APOE ε4 status in this context.
RESULTS: With one of the scores, higher adherence to the EAT-Lancet diet was associated with a reduced risk of AD and all-cause dementia. Moreover, the results suggest an interplay between the EAT-Lancet diet and APOE ε4 status. A risk-reducing effect was observed among APOE ε4 non-carriers with three of the scores in relation to AD, and with five of the scores in relation to all-cause dementia. No associations were observed among APOE ε4 carriers, or in relation to VaD.
CONCLUSION: The results indicate a risk reducing effect of adhering to the EAT-Lancet diet among APOE ε4 non-carriers, and no negative effects on dementia risk were detected. Future studies should consider the potentially modifying effect of APOE ε4 status, and the implications of methodological differences in measuring adherence to the EAT-Lancet diet.
CITATION:
Jessica Samuelsson ; Isabelle Glans ; Anna Stubbendorff ; Ulrika Ericson ; Sebastian Palmqvist ; Oskar Hansson ; Emily Sonestedt (2025): Associations between the EAT-Lancet planetary health diet and incident dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100166
THE ROLE OF SERUM VITAMINS IN MEDIATING THE EFFECT OF NEURODEGENERATIVE DISEASES ON SUBCORTICAL BRAIN VOLUME
Haonan Li, Meng Cheng, Nannan Zhang, Siqi Wang, Caihua Ye, Haodong Li, Shengnan Wang, Zirui Wang, Xuan Yang, Zhixuan Liu, Xingyu Zhang, Jiayuan Xu, Qiang Xu, Junping Wang
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Neurodegenerative diseases (NDs) lead to a progressive loss of neuronal cells and link to atrophy of subcortical brain structures, but the causal intermediates are not known. To test whether major NDs (Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis) causally affects subcortical atrophy, and whether serum vitamin level play a mediating role in this process.
METHODS: Using large-scale genome-wide association study (GWAS) summary data, we performed two-sample Mendelian randomization (MR) to assess the causal effect of NDs on the volume of seven subcortical structures, and then adopted two-step multivariable MR approach to quantify the proportion of the effect of NDs on the volume of subcortical regions mediated by serum vitamin level. Finally, we utilized animal experiments to validate results and explored the potential molecular mechanisms.
RESULTS: Genetically predicted AD was associated with atrophy of the nucleus accumbens (NAc) (β = -0.09; p = 5.13 × 10–5), amygdala (β = -0.07; p = 8.44 × 10–4), and hippocampus (β = -0.07; p = 0.001), as well as with low serum vitamin D level (β = -0.02; p = 6.84 × 10–6). Specifically, decreased serum vitamin D level mediated 3.99 % (95 % CI: -0.006 to -5.82 × 10–5) and 3.97 % (95 % CI: -0.007 to -2.94 × 10–4) of the total effect of AD on hippocampal and NAc atrophy, respectively. Animal experiments further confirmed significant delays in hippocampal and NAc atrophy, a significant reduction of β-amyloid deposits and an increase of vitamin D receptor expression in hippocampus in AD mice with high-dose vitamin D diet.
CONCLUSIONS: These findings provide important insights into the effect sizes of vitamin D-mediated roles in AD and atrophy of subcortical structures. Interventions to increase serum vitamin D levels at a population level might attenuate damage to hippocampus in patients with AD.
CITATION:
Haonan Li ; Meng Cheng ; Nannan Zhang ; Siqi Wang ; Caihua Ye ; Haodong Li ; Shengnan Wang ; Zirui Wang ; Xuan Yang ; Zhixuan Liu ; Xingyu Zhang ; Jiayuan Xu ; Qiang Xu ; Junping Wang (2025): The role of serum vitamins in mediating the effect of neurodegenerative diseases on subcortical brain volume. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100155
OPPOSITE CAUSAL EFFECTS OF TYPE 2 DIABETES AND METFORMIN ON ALZHEIMER\'S DISEASE
Dongming Liu, Hongbao Cao, Ancha Baranova, Chenxin Xu, Fuquan Zhang
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Type 2 diabetes (T2D) is commonly co-morbid with Alzheimer's disease (AD). However, it remains unclear whether T2D itself or the antidiabetic drug metformin contributes to the progression of AD.
OBJECTIVE: This study aimed to investigate the overall and independent effects of T2D and metformin use on the risk of AD.
METHODS: Summary genome-wide association study datasets were utilized for the Mendelian randomization (MR) and multivariable MR (MVMR) analyses, including ones for T2D (N = 455,017), metformin (N = 456,276), and AD (N = 453,733). Additionally, using the proportional imbalance method, we analyzed AD-related adverse drug events in the FDA Adverse Event Reporting System (FAERS) database (covering Q1 2004 to Q2 2024).
RESULTS: Our two-sample MR analysis indicated that T2D is not associated with the risk of AD (OR: 1.03, CI: 0.99–1.08, P = 0.128). However, while not statistically significant, genetic signature for metformin exposure demonstrated a trend toward an increased risk of AD (OR: 1.05, CI: 1.00–1.09, P = 0.053). Interestingly, in MVMR analysis, which evaluates independent effects of T2D and metformin exposure on T2D, we found a robust association of T2D with a decrease in the risk of AD (OR: 0.82, CI: 0.68–0.98, P = 0.031), while the use of metformin was associated with a higher risk of AD (OR: 1.26, CI: 1.06–1.50, P = 9.45E-3). In the FAERS database, a total of 228,283 metformin-related adverse event reports from 67,742 cases were found. For metformin as the target drug and AD as the target adverse event, signal analysis reported 29 cases of AD (ROR: 0.83, 95 % CI: 0.58–1.19, P = 0.3126).
CONCLUSIONS: Our study reveals the opposite independent causal effects of T2D and metformin exposure on AD. These findings highlight the importance of assessing AD risk when prescribing metformin to patients with T2D.
CITATION:
Dongming Liu ; Hongbao Cao ; Ancha Baranova ; Chenxin Xu ; Fuquan Zhang (2025): Opposite causal effects of type 2 diabetes and metformin on Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100129
LATENT COGNITIVE PROFILES AND THEIR ASSOCIATIONS WITH INSTRUMENTAL ACTIVITIES OF DAILY LIVING AMONG OLDER ADULTS WITHOUT DEMENTIA: A UNITED STATES NATIONAL CROSS-SECTIONAL STUDY
Jiaying Li, Sarah L. Szanton, Junxin Li
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Conventional dichotomous classifications of cognitive status in older adults (normal vs impaired) may obscure distinct domain-specific deficits. Identifying nuanced cognitive profiles could enable personalized interventions, particularly when tailored to instrumental activities of daily living (IADLs).
OBJECTIVES: To identify distinct cognitive profiles in older adults without dementia and assess their associations with overall and domain-specific IADL performance.
DESIGN/SETTING/PARTICIPANTS: Cross-sectional data from 2219 adults aged ≥65 years without dementia in the nationally representative National Health and Aging Trends Study.
MEASUREMENTS: Latent profile analysis classified participants across six cognitive domains: episodic memory, executive function, orientation, psychomotor function, visual attention, and working memory. Logistic and linear regression models with Holm-Bonferroni corrections evaluated relationships between cognitive profiles and IADL performance.
RESULTS: Five profiles emerged: Profile 1: Overall intact (50.5 % of participants); Profile 2: Isolated moderate orientation impairment (15.6 %); Profile 3: Mild global impairment with preserved orientation (22.0 %); Profile 4: Mild global impairment with significant orientation impairment (5.5 %); Profile 5: Moderate global impairment (6.2 %). Compared with Profile 1, all other profiles exhibited significantly higher overall IADL difficulty and were more likely to experience challenges with shopping, medication management, meal preparation, and banking (all adjusted p < 0.05). Profile 4 had the highest odds for difficulties with shopping (OR, 2.19; 95 % CI, 1.41–3.38; adjusted p = 0.005) and banking (OR, 3.98; 95 % CI, 2.62–6.04; adjusted p < 0.001), whereas Profile 5 showed the greatest risk for medication management (OR, 2.55; 95 % CI, 1.66–3.90; adjusted p < 0.001) and meal preparation (OR, 2.22; 95 % CI, 1.49–3.31; adjusted p = 0.001).
CONCLUSION: Nearly half of older adults without dementia exhibit distinct cognitive profiles warranting tailored interventions. Profile 5 requires comprehensive strategies, whereas Profiles 2, 3, and 4 may benefit from orientation-targeted and intensity-varied training in other cognition domain. Incorporating specific IADL tasks (e.g., meal preparation, medication management for Profile 5 and shopping, banking for Profile 4) into cognitive interventions may concurrently enhance cognitive health and functional independence.
CITATION:
Jiaying Li ; Sarah L. Szanton ; Junxin Li (2025): Latent cognitive profiles and their associations with instrumental activities of daily living among older adults without dementia: A United States national cross-sectional study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100162
THE COST-EFFECTIVENESS OF AN ONLINE INTERVENTION TO PREVENT DEMENTIA: RESULTS FROM THE MAINTAIN YOUR BRAIN (MYB) RANDOMISED CONTROLLED TRIAL
Heidi J Welberry, Li-Jung Elizabeth Ku, Sophy TF Shih, Louisa R Jorm, Maria Fiatarone Singh, Michael Valenzuela, Jeewani Anupama Ginige, Kaarin J. Anstey, Perminder S. Sachdev, John J McNeil, Nicola T Lautenschlager, Megan Heffernan, Tiffany Chau, Henry Brodaty
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: The Maintain Your Brain (MYB) randomised controlled trial (RCT) examined the effect of a multi-domain internet-based dementia prevention program against a control group (information only).
OBJECTIVES: A cost-effective analysis (CEA) quantified the differences in costs (direct healthcare and program costs) and effectiveness outcomes between the intervention and control groups from a healthcare sector perspective.
DESIGN: An economic evaluation was conducted alongside the MYB RCT over three years.
SETTING: Australians aged 55–77 years with at least 2 identified remediable risk factors for cognitive decline/dementia recruited from communities in New South Wales.
PARTICIPANTS: There were 3,025 participants in the intervention group and 3,033 in the control group with available linked healthcare data via the Sax Institute's 45 and Up Study out of the 6104 enrolled in the trial (99.2% of total cohort).
INTERVENTION: The MYB trial comprised a personalised schedule of online coaching in physical activity, nutrition, cognitive activity, and depression or anxiety management.
MEASUREMENTS: The two effectiveness outcomes were global cognition composite (GCC) scores and the Australian National University-Alzheimer's Disease Risk Index –short form (ANU-ADRI-SF) questionnaire scores. Costs included MYB program costs and the direct healthcare costs incurred by the MYB participants. All costs were reported in Australian dollars (AUD$) during the trial period. The time horizon of this analysis was 3 years after randomisation (2018-2021). Incremental cost-effectiveness ratio (ICERs) between the intervention and the control groups were calculated by comparing the average difference in costs to a mean difference in z score for GCC and ANU-ADRI-SF score using the bootstrapped means and 95% Confidence Intervals.
RESULTS: The total unadjusted program and healthcare costs over three years were similar between groups (AUD$16,521 per person in the control group and AUD$16,473 in the intervention group). After adjusting for baseline characteristics, the average difference between groups in total cost per person at three years was not statistically different: AUD$467 favouring the control group (95%CI: -$552 - $1585). This was compared to a significant mean difference (improvement) in GCC z score at three years of 0.18 (95%CI: 0.13, 0.23) and -0.57 (95%CI: -0.95, -0.24) point difference in ANU-ADRI-SF for the intervention versus control. The base case ICERs were AUD$2,568 per 1 standard deviation in z score and $823 per reduction of 1 ANU-ADRI-SF point. With 1000 bootstrapped replications, the scatterplots of ICER ellipses suggest that the MYB intervention was more effective than the control group and with no significant difference in overall healthcare costs.
CONCLUSION: The MYB trial showed cost-effectiveness for preventing cognitive decline and reducing dementia risk. Longer-term follow-up and dissemination to other cohorts is needed to confirm the impact on preventing future cases of dementia and relevance to other socio-economic and cultural/ethnic groups than those enrolled in the original trial.
CITATION:
Heidi J Welberry ; Li-Jung Elizabeth Ku ; Sophy TF Shih ; Louisa R Jorm ; Maria Fiatarone Singh ; Michael Valenzuela ; Jeewani Anupama Ginige ; Kaarin J. Anstey ; Perminder S. Sachdev ; John J McNeil ; Nicola T Lautenschlager ; Megan Heffernan ; Tiffany Chau ; Henry Brodaty (2025): The cost-effectiveness of an online intervention to prevent dementia: Results from the Maintain Your Brain (MYB) randomised controlled trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100151
PATIENT MANAGEMENT PATHWAYS IN DEMENTIA – RESOURCE UTILISATION, DIAGNOSIS AND DRUG TREATMENT IN THE STOCKHOLM REGION, SWEDEN
Emil Aho, Dorota Religa, Mozhu Ding, Bengt Winblad, Linus Jönsson, Karin Modig
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: New diagnostic and therapeutic options for Alzheimer's disease are beginning to be introduced and expected igto become more widely available in the coming years. Improved understanding of current pathways in diagnosis and initial care of patients with dementia can help inform choices around how best to integrate new technologies in existing care structures.
OBJECTIVES: The aim of this study is to describe the care management pathways defined by the involvement of specialist and primary care for individuals with newly diagnosed dementia. It also seeks to characterise individuals in different management pathways based on resource use prior to diagnosis, the type of dementia diagnosis received, and the proportion who receive symptomatic anti-dementia drug treatment.
DESIGN: Observational cohort study.
SETTING: Stockholm region, Sweden.
PARTICIPANTS: All newly diagnosed dementia cases between 1st January 2018 to 30th June 2020 (n = 9,781). Dementia diagnoses in primary care were based on Regional Stockholm health care database and diagnoses in specialist care were based on the National Patient Register in Sweden.
MEASUREMENTS: Care management pathways were categorized into three groups: primary care only (diagnosed and followed up in primary care), specialist, no follow-up (diagnosed in specialist care but not followed up in specialist care), and specialist with follow-up (diagnosed and followed up in specialist care). These classifications were based on patients’ care episodes from the date of diagnosis and the subsequent 18 months. age at diagnosis, resource utilisation one-year prior diagnosis and diagnosis given and symptomatic anti-dementia treatment 18 months after initial diagnosis.
RESULTS: A total of 9,781 newly diagnosed dementia cases were identified. In the 18 months following diagnosis, 63 % of patients were diagnosed either partly or fully in specialist care, while 37 % were diagnosed solely in primary care. Patients diagnosed and managed only in primary care were older, spent more days in hospital, and received more social care in the year preceding their diagnosis. Their total care costs were also the highest. Alzheimer's disease was the most common diagnosis (48 %), while 27 % had an unspecified dementia diagnosis, varying by care setting (61 % for patients managed in primary care only and 6 % for patients diagnosed and followed up in specialist care). Overall, 47 % of patients received symptomatic anti-dementia treatment, with the highest share for patients diagnosed and followed up in specialist care (73 %) and the lowest in primary care only (19 %). Diagnosis varied by age and care setting Alzheimer's was most common in settings involving specialist care, whereas unspecified dementia was more common in primary care only regardless of age.
CONCLUSION: The findings that patients managed exclusively in primary care were older, had higher pre-diagnosis resource utilisation, and were less likely to receive specific diagnoses or anti-dementia treatments highlight the crucial role of primary care in diagnosing and managing dementia among older individuals with complex needs. Further research is needed to explore primary care's role in diagnosis and treatment across diverse healthcare systems.
Future research is needed to explore whether and how new diagnostic tools and treatment for AD could facilitate timely diagnosis and care for older individuals with dementia in primary care.
CITATION:
Emil Aho ; Dorota Religa ; Mozhu Ding ; Bengt Winblad ; Linus Jönsson ; Karin Modig (2025): Patient management pathways in dementia – Resource utilisation, diagnosis and drug treatment in the Stockholm region, Sweden. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100132
ASSOCIATION BETWEEN THE USE OF INFORMATION AND COMMUNICATION TECHNOLOGY AND COGNITIVE DECLINE STRATIFIED BY SOCIAL ISOLATION: THE OTASSHA STUDY
Keigo Imamura, Hisashi Kawai, Manami Ejiri, Hiroyuki Sasai, Kazushige Ihara, Harumi Nakada, Atsushi Araki, Hirohiko Hirano, Yoshinori Fujiwara, Takao Suzuki, Shuichi Obuchi
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Prevention of dementia is crucial for reducing its social burden. Social isolation is a known risk factor for dementia. The use of information and communication technology is associated with reduced cognitive decline. However, longitudinal associations of the use of information and communication technology with cognitive function remain unknown, especially for older adults who are socially isolated and at a high risk of cognitive decline.
OBJECTIVES: To investigate the association between the use of information and communication technology and changes in cognitive function among older adults with and without social isolation.
DESIGN: Longitudinal observational study.
SETTING: Data was obtained for two cohorts of community-dwelling older adults aged 65 years with no cognitive impairment (Mini-Mental State Examination score ≥24) at baseline.
PARTICIPANTS: Participants were defined as those who completed baseline assessments of the use of information and communication technology, social isolation, and cognitive function and underwent at least one follow-up assessment of cognitive function in a follow-up survey conducted annually through 2023.
MEASUREMENTS: The use of information and communication technology was measured using the technology usage sub-items of the Japan Science and Technology Agency Index of Competence. Cognitive function and social isolation were assessed using the Mini-Mental State Examination and the six-item Lubben Social Network Scale, respectively. Data from the two cohorts were combined to examine the association between the use of information and communication technology and changes in cognitive function, as well as the association between the use of information and communication technology and the incidence of cognitive decline (Mini-Mental State Examination <24), using mixed effects models and Cox proportional hazards models, respectively. These analyses were conducted separately based on social isolation.
RESULTS: A total of 1,322 participants (mean age: 72.3 years, 39 % male) were included in the final analysis. The median follow-up period was 3.9 years. Individuals who used information and communication technology experienced a slower rate of cognitive decline than non-users (-0.09, 95 % confidence interval: -0.11 to -0.07 vs. -0.18, 95 % confidence interval: -0.21 to -0.15). In addition, information and communication technology use was associated with a significantly lower risk of cognitive decline (hazard ratio: 0.73, 95 % confidence interval: 0.70–0.76). This association remained consistent among older adults with social isolation (hazard ratio: 0.91, 95 % confidence interval: 0.85–0.97).
CONCLUSIONS: The use of information and communication technology was associated with a reduced risk of cognitive decline, even among socially isolated older adults. Creating an environment that enables effective ICT use with appropriate support may help preserve cognitive function in aging populations.
CITATION:
Keigo Imamura ; Hisashi Kawai ; Manami Ejiri ; Hiroyuki Sasai ; Kazushige Ihara ; Harumi Nakada ; Atsushi Araki ; Hirohiko Hirano ; Yoshinori Fujiwara ; Takao Suzuki ; Shuichi Obuchi (2025): Association between the use of information and communication technology and cognitive decline stratified by social isolation: The Otassha study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100138
LONGITUDINAL ASSOCIATIONS OF CAROTID ARTERY STIFFNESS WITH PROGRESSION OF CEREBROVASCULAR DISEASE, INCIDENT DEMENTIA AND COGNITIVE DECLINE IN OLDER ADULTS
Caroline Robert, Lieng-Hsi Ling, Eugene S.J. Tan, Narayanaswamy Venketasubramanian, Shir Lynn Lim, Lingli Gong, Josephine Lunaria Berboso, Arthur Mark Richards, Christopher Chen, Saima Hilal, Josephine Lunaria Berboso, Arthur Mark Richards, Christopher Chen, Saima Hilal
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: Carotid artery stiffness is associated with cerebrovascular disease (CeVD) and cognitive impairment, but evidence for its longitudinal effects on progression of CeVD and cognitive decline are limited.
OBJECTIVES: To evaluate the longitudinal associations of carotid artery stiffness with CeVD progression, incident dementia, and cognitive decline.
DESIGN: Longitudinal analyses from a memory-clinic cohort with a follow-up of 2 years.
SETTING: A memory-clinic study.
PARTICIPANTS: 194 participants (mean age=80, 63 % female) with or without cognitive impairments provided consent to take part in the study.
MEASUREMENTS: Participants underwent carotid ultrasonography, brain MRI, and neuropsychological assessments were at baseline and follow-up. Carotid stiffness measures included ß-index, elastic modulus (Ep), and pulse wave velocity-ß (PWV-ß). CeVD markers included white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs) and cortical infarcts. Cognition was assessed with a neuropsychological battery.
RESULTS: After 2 years, incident CeVD cases included lacunes (15.7 %), CMBs (23.8 %), and cortical infarcts (7.6 %). ß-index (ß=0.78, p < 0.001), Ep (ß=0.94, p < 0.001), and PWV-ß (ß=0.15, p = 0.003) were independently associated with WMH progression. Ep (ß=-0.15, p = 0.007) and PWV-ß (ß=-3.68, p = 0.007) were independently associated with visuomotor speed decline. No association was found with incident lacunes, CMBs or dementia.
CONCLUSION: Carotid stiffness progression is associated with WMH progression and visuomotor speed decline.
CITATION:
Caroline Robert ; Lieng-Hsi Ling ; Eugene S.J. Tan ; Narayanaswamy Venketasubramanian ; Shir Lynn Lim ; Lingli Gong ; Josephine Lunaria Berboso ; Arthur Mark Richards ; Christopher Chen ; Saima Hilal (2025): Longitudinal associations of carotid artery stiffness with progression of cerebrovascular disease, incident dementia and cognitive decline in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100127
MULTI-OMICS ANALYSIS OF DRUGGABLE GENES TO FACILITATE ALZHEIMER\'S DISEASE THERAPY: A MULTI-COHORT MACHINE LEARNING STUDY
Jichang Hu, Yong Luo, Xiaochuan Wang
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: The swift rise in the prevalence of Alzheimer's disease (AD) alongside its significant societal and economic impact has created a pressing demand for effective interventions and treatments. However, there are no available treatments that can modify the progression of the disease.
METHODS: Eight AD brain tissues datasets and three blood datasets were obtained. Consensus clustering was utilized as a method to discern the various subtypes of AD. Then, module genes were screened using weighted correlation network analysis (WGCNA). Furthermore, screening hub genes was conducted through machine-learning analyses. Finally, A comprehensive analysis using a systematic approach to druggable genome-wide Mendelian randomization (MR) was conducted.
RESULTS: Two AD subclasses were identified, namely cluster.A and cluster.B. The levels of gamma secretase activity, beta secretase activity, and amyloid-beta 42 were found to be significantly elevated in patients classified within cluster A when compared to those in cluster B. Furthermore, by utilizing the differentially expressed genes shared among these clusters, along with identifying druggable genes and applying WGCNA to these subtypes, we were able to develop a scoring system referred to as DG.score. This scoring system has demonstrated remarkable predictive capability for AD when evaluated against multiple datasets. Besides, A total of 30 distinct genes that may serve as potential drug targets for AD were identified across at least one of the datasets investigated, whether derived from brain samples or blood analyses. Among the identified genes, three specific candidates that are considered druggable (LIMK2, MAPK8, and NDUFV2) demonstrated significant expression levels in both blood and brain tissues. Furthermore, our research also revealed a potential association between the levels of LIMK2 and concentrations of CSF Aβ (OR 1.526 (1.155–2.018)), CSF p-tau (OR 1.106 (1.024–01.196)), and hippocampal size (OR 0.831 (0.702–0.948)).
CONCLUSIONS: This study provides a notable advancement to the existing literature by offering genetic evidence that underscores the potential therapeutic advantages of focusing on the druggable gene LIMK2 in the treatment of AD. This insight not only contributes to our understanding of AD but also guides future drug discovery efforts.
CITATION:
Jichang Hu ; Yong Luo ; Xiaochuan Wang (2025): Multi-omics analysis of druggable genes to facilitate Alzheimer's disease therapy: A multi-cohort machine learning study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100128
CHRONOTYPE AS A POTENTIAL RISK FACTOR FOR COGNITIVE DECLINE: THE MEDIATING ROLE OF SLEEP QUALITY AND HEALTH BEHAVIOURS IN A 10-YEAR FOLLOW-UP STUDY
A.N. Wenzler, A.C. Liefbroer, R.C. Oude Voshaar, N. Smidt
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryBACKGROUND: – With rising life expectancies and ageing populations worldwide, preserving cognitive health is an urgent global priority. Chronotype could be a potential risk factor for cognitive decline, potentially through mediators sleep quality, alcohol intake, physical activity, and smoking.
METHODS: – This study used data from participants aged 40 years and older from the Lifelines cohort study (n = 23,798). Chronotype, assessed with the Munich ChronoType Questionnaire, was included as a continuous score of mid-point sleep corrected for sleep debt on workdays. Multiple linear regression examined the association between chronotype and cognitive decline, including moderation by age, educational attainment, and sex. The KHB-method was applied to test mediation by sleep quality, alcohol intake, physical activity, and smoking.
OUTCOMES: – Cognition was assessed with the Ruff Figural Fluency Test (RFFT), measuring non-verbal fluency and executive functioning. Cognitive decline was calculated by subtracting the RFFT sum score at baseline from the 10-year follow-up score.
RESULTS: – Chronotype was associated with cognitive decline. Educational attainment, but not age or sex, moderated the relationship. No significant associations were observed in the low- (0.07, 95 % CI: -0.44, 0.57) or middle- (-0.41, 95 % CI: -0.88, 0.06) educational groups. In the high-educational group each one-hour increase in chronotype corresponded to a 0.80-point decline in cognition per decade (95 % CI: -1.34, -0.26). In this group, sleep quality and current smoking mediated 13.52 % and 18.64 % of the association, respectively.
INTERPRETATION: – Chronotype was associated with greater decline in non-verbal fluency and executive functioning among higher educated participants, highlighting the importance of targeted prevention strategies.
CITATION:
A.N. Wenzler ; A.C. Liefbroer ; R.C. Oude Voshaar ; N. Smidt (2025): Chronotype as a potential risk factor for cognitive decline: The mediating role of sleep quality and health behaviours in a 10-year follow-up study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100168
LONG-TERM CUMULATIVE PHYSICAL ACTIVITY ASSOCIATED WITH LESS COGNITIVE DECLINE: EVIDENCE FROM A 16-YEAR COHORT STUDY
Suhang Song, Meng Hsuan Sung, Diana Diaz, Zhuofan Lin, Allan D. Tate, Zhuo Chen, Janani Rajbhandari-Thapa, Grace Bagwell Adams, M. Mahmud Khan, Ye Shen, Lisa M. Renzi-Hammond, Yinzi Jin
J Prev Alz Dis 2025;6(12)
Show summaryHide summaryINTRODUCTION: Physical activity (PA) has been reported to delay cognitive decline. However, the role of long-term, cumulative PA (cPA) in cognitive decline remains unclear.
METHODS: This longitudinal study obtained data from Health and Retirement Study, 2004-2020. Global cognition was operationalized as the sum of memory and executive function scores on a battery of cognitive tests. cPA was operationalized as the area under the curve of the metabolic equivalent of tasks (MET) adjusted PA. Generalized linear mixed models were fitted to examine the associations between cPA and cognitive change.
RESULTS: This study included 13,450 cognitively healthy participants, with a mean follow-up duration of 11.06 (SD=4.91) years. Higher cPA was associated with delayed declines in global cognition (p<.001), memory (p<.001) and executive function (p<.001), and such protective benefits grew over the 16-year study period. Longer PA engagement was associated with progressively delayed cognitive decline.
CONCLUSION: PA engagement over long timeframes may better maintain cognitive performance.
CITATION:
Suhang Song ; Meng Hsuan Sung ; Diana Diaz ; Zhuofan Lin ; Allan D. Tate ; Zhuo Chen ; Janani Rajbhandari-Thapa ; Grace Bagwell Adams ; M. Mahmud Khan ; Ye Shen ; Lisa M. Renzi-Hammond ; Yinzi Jin (2025): Long-term cumulative physical activity associated with less cognitive decline: Evidence from a 16-year cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100194
LETTER TO THE EDITOR: DISPARITIES IN OUT-OF-POCKET COSTS FOR DISEASE-MODIFYING THERAPY UNDER JAPAN\'S UNIVERSAL HEALTH INSURANCE SYSTEM
Kenichiro Sato, Ryoko Ihara, Yoshiki Niimi, Saki Nakashima, Atsushi Iwata, Takeshi Iwatsubo
J Prev Alz Dis 2025;6(12)
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CITATION:
Kenichiro Sato ; Ryoko Ihara ; Yoshiki Niimi ; Saki Nakashima ; Atsushi Iwata ; Takeshi Iwatsubo (2025): Letter to the Editor: Disparities in out-of-pocket costs for disease-modifying therapy under Japan's universal health insurance system. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100170
LETTER TO THE EDITOR: HERPES ZOSTER AND DEMENTIA RISK
Shih-Wei Lai, Kuan-Fu Liao
J Prev Alz Dis 2025;6(12)
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CITATION:
Shih-Wei Lai ; Kuan-Fu Liao (2025): Letter to the Editor: Herpes zoster and dementia risk. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100198
REPLY TO THE LETTER TO THE EDITOR: HERPES ZOSTER AND DEMENTIA RISK
Lorenzo Blandi, Paola Bertuccio, Carlo Signorelli, Helmut Brand, Timo Clemens, Cristina Renzi, Anna Odone
J Prev Alz Dis 2025;6(12)
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CITATION:
Lorenzo Blandi ; Paola Bertuccio ; Carlo Signorelli ; Helmut Brand ; Timo Clemens ; Cristina Renzi ; Anna Odone (2025): Reply to the Letter to the Editor: Herpes Zoster and Dementia Risk. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100197
RESPONSE TO “MULTI-OMICS ANALYSIS OF DRUGGABLE GENES TO FACILITATE ALZHEIMER\'S DISEASE THERAPY: A MULTI-COHORT MACHINE LEARNING STUDY”
Jichang Hu
J Prev Alz Dis 2025;6(12)
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CITATION:
Jichang Hu (2025): Response to “Multi-omics analysis of druggable genes to facilitate Alzheimer's disease therapy: A multi-cohort machine learning study”. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100250
COMMENT ON “MULTI-OMICS ANALYSIS OF DRUGGABLE GENES TO FACILITATE ALZHEIMER\'S DISEASE THERAPY: A MULTI-COHORT MACHINE LEARNING STUDY”
Jihao Xue, Yitian Chen, Ligang Chen, Qijia Yin
J Prev Alz Dis 2025;6(12)
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