07/2025 journal articles
EDITORIAL: ASTROCYTES PROVIDE A UNIQUE BIOMARKER FOR ALZHEIMER’S AND OTHER PATHOLOGIES
Eric Siemers
J Prev Alz Dis 2025;7(12)
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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
EDITORIAL: BREAKING BARRIERS: DELIVERING THERAPEUTICS TO THE BRAIN IN ALZHEIMER’S DISEASE
Bart De Strooper, Philip Scheltens, Stephen Salloway
J Prev Alz Dis 2025;7(12)
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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
EDITORIAL: EXERCISE FOR DEMENTIA PREVENTION: EVIDENCE FOR A FLEXIBLE PRESCRIPTION
Mikel Izquierdo
J Prev Alz Dis 2025;7(12)
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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: PHYSICAL ACTIVITY AND ALZHEIMER’S DISEASE: A CALL FOR EVIDENCE INCORPORATION
Juan Luis Sánchez-Sánchez, Philipe de Souto Barreto
J Prev Alz Dis 2025;7(12)
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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
EDITORIAL: SERUM BDNF AND PROGRESSION TO MCI IN COGNITIVELY NORMAL OLDER ADULTS A PROSPECTIVE COHORT STUDY
Gary A. Rosenberg
J Prev Alz Dis 2025;7(12)
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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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryThe 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
DOSE- AND PATTERN- PHYSICAL ACTIVITY IS ASSOCIATED WITH LOWER RISK OF DEMENTIA
Yan Wang, Fangyu Li, Shuman Cao, Jianping Jia
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
LIFETIME WALKING AND ALZHEIMER’S PATHOLOGY: A LONGITUDINAL STUDY IN OLDER ADULTS
Jee Wook Kim, Musung Keum, Min Soo Byun, Dahyun Yi, So Yeon Jeon, Joon Hyung Jung, Nayeong Kong, Yoon Young Chang, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Koung Mi Kang, Chul-Ho Sohn, Yun-Sang Lee, Yu Kyeong Kim, Dong Young Lee, KBASE Research Group
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryIMPORTANCE: While many studies have shown that greater amounts or longer durations of walking are associated with a lower risk of Alzheimer’s disease (AD) or cognitive decline in older adults, the neuropathological basis for this is not yet fully understood.
OBJECTIVE: To examine the relationship between walking intensity and duration and longitudinal changes in Alzheimer’s disease (AD)-related brain pathologies, including Aβ and tau accumulation, neurodegeneration, and white matter hyperintensity (WMH).
DESIGN: Data were drawn from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, a longitudinal cohort study (initiated in 2014).
SETTING: Community and memory clinic setting.
PARTICIPANTS: One hundred fifty-one older adults.
MAIN OUTCOME AND MEASURES: Participants underwent baseline and 4-year follow-up neuroimaging assessments. Lifetime walking, as measured using the Lifetime Total Physical Activity Questionnaire, was categorized by intensity (high vs. low) and duration (short ≤360 min/week vs. long >360 min/week), forming four combined walking groups. Aβ and tau deposition, neurodegeneration, and WMH volume were assessed via PET/MRI.
RESULTS: Long-duration or high-intensity walking was associated with significantly reduced Aβ accumulation over 4 years. The high-combined walking group showed similar benefits, while medium-combined groups did not. The effect was significant only in the early life-initiated walking subgroup. No associations were found with tau, neurodegeneration, or WMH volume.
CONCLUSIONS: Long-duration, high-intensity walking may reduce brain Aβ accumulation, potentially lowering AD risk, particularly when initiated before late life.
CITATION:
Jee Wook Kim ; Musung Keum ; Min Soo Byun ; Dahyun Yi ; So Yeon Jeon ; Joon Hyung Jung ; Nayeong Kong ; Yoon Young Chang ; Gijung Jung ; Hyejin Ahn ; Jun-Young Lee ; Koung Mi Kang ; Chul-Ho Sohn ; Yun-Sang Lee ; Yu Kyeong Kim ; Dong Young Lee ; ; , KBASE Research Group m ; Show more ; (2025): Lifetime walking and Alzheimer’s pathology: A longitudinal study in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100203
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryDespite 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
PLASMA P-TAU217 PREDICTING BRAIN-WIDE TAU ACCUMULATION IN PRECLINICAL AD
Hasom Moon, Xi Chen, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryAlzheimer’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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBlood 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryINTRODUCTION: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryINTRODUCTION: 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
LETTER TO THE EDITOR: COMMENT ON \"HEARING LOSS, DIET, AND COGNITIVE DECLINE: INTERCONNECTIONS FOR DEMENTIA PREVENTION\"
Cuiqing Zhao, Jian Gong, Jia Huang
J Prev Alz Dis 2025;7(12)
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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
REPLY TO THE LETTER TO THE EDITOR: HEARING LOSS, DIET, AND COGNITIVE DECLINE: INTERCONNECTIONS FOR DEMENTIA PREVENTION
Xiaoran Liu, Uzma S. Akhtar
J Prev Alz Dis 2025;7(12)
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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
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
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryAmyloid-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
ERRATUM TO “INTERCEPT-AD, A PHASE 1 STUDY OF INTRAVENOUS SABIRNETUG IN PARTICIPANTS WITH MILD COGNITIVE IMPAIRMENT OR MILD DEMENTIA DUE TO ALZHEIMER\'S DISEASE”
Eric Siemers, Todd Feaster, Gopalan Sethuraman, Karen Sundell, Vladimir Skljarevski, Erika N. Cline, Hao Zhang, Jasna Jerecic, Lawrence S. Honig, Stephen Salloway, Reisa Sperling, Mirjam N. Trame, Michael G. Dodds, Kimball Johnson
J Prev Alz Dis 2025;7(12)
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CITATION:
Eric Siemers ; Todd Feaster ; Gopalan Sethuraman ; Karen Sundell ; Vladimir Skljarevski ; Erika N. Cline ; Hao Zhang ; Jasna Jerecic ; Lawrence S. Honig ; Stephen Salloway ; Reisa Sperling ; Mirjam N. Trame ; Michael G. Dodds ; Kimball Johnson (2025): Erratum to “INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease”. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100213
ERRATUM TO “BIOFLUID BIOMARKER CHANGES FOLLOWING TREATMENT WITH SABIRNETUG (ACU193) IN INTERCEPT-AD, A PHASE 1 TRIAL IN EARLY ALZHEIMER\'S DISEASE”
Erika N. Cline, Daniel Antwi-Berko, Karen Sundell, Elizabeth Johnson, Maddelyn Hyland, Hao Zhang, Hugo Vanderstichele, June Kaplow, Robert A. Dean, Erik Stoops, Eugeen Vanmechelen, Marleen J.A. Koel-Simmelink, Charlotte E. Teunissen, Gopalan Sethuraman, Todd Feaster, Eric Siemers, Jasna Jerecic
J Prev Alz Dis 2025;7(12)
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CITATION:
Erika N. Cline ; Daniel Antwi-Berko ; Karen Sundell ; Elizabeth Johnson ; Maddelyn Hyland ; Hao Zhang ; Hugo Vanderstichele ; June Kaplow ; Robert A. Dean ; Erik Stoops ; Eugeen Vanmechelen ; Marleen J.A. Koel-Simmelink ; Charlotte E. Teunissen ; Gopalan Sethuraman ; Todd Feaster ; Eric Siemers ; Jasna Jerecic (2025): Erratum to “Biofluid biomarker changes following treatment with sabirnetug (ACU193) in INTERCEPT-AD, a phase 1 trial in early Alzheimer's disease”. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100217