Ahead of print articles
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
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BACKGROUND: 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
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
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
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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
LETTER TO THE EDITOR: HERPES ZOSTER AND DEMENTIA RISK
Shih-Wei Lai, Kuan-Fu Liao
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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
EDITORIAL: HERPES ZOSTER AND DEMENTIA : MORE EVIDENCES FOR A CAUSAL LINK
Jean-François Dartigues, Morgane Linard
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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: BRAIN HEALTH PRO/SANTE CERVEAU PRO: THE DEVELOPMENT OF A WEB-BASED PROGRAM FOR DEMENTIA LITERACY AND RISK FACTOR REDUCTION
Alex Bahar-Fuchs
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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
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
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INTRODUCTION: 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
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
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
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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
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
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
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BACKGROUND: – 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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BACKGROUND: 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
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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
SAMPLE SIZE ESTIMATES FOR BIOMARKER-BASED OUTCOME MEASURES IN CLINICAL TRIALS IN AUTOSOMAL DOMINANT ALZHEIMER\'S DISEASE
David M Cash, Katy E Morgan, Antoinette O\'Connor, Thomas D Veale, Ian B Malone, Teresa Poole, Tammie LS Benzinger, Brian A Gordon, Laura Ibanez, Yan Li, Jorge J. Llibre-Guerra, Eric McDade, Guoqiao Wang, Jasmeer P Chhatwal, Gregory S Day, Edward Huey, Mathias Jucker, Johannes Levin, Yoshiki Niimi, James M Noble, Jee Hoon Roh, Racquel Sánchez-Valle, Peter R Schofield, Randall J Bateman, Chris Frost, Nick C Fox, The Dominantly Inherited Alzheimer Network (DIAN)
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INTRODUCTION: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.
METHODS: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).
RESULTS: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).
DISCUSSION: Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.
CITATION:
David M Cash ; Katy E Morgan ; Antoinette O'Connor ; Thomas D Veale ; Ian B Malone ; Teresa Poole ; Tammie LS Benzinger ; Brian A Gordon ; Laura Ibanez ; Yan Li ; Jorge J. Llibre-Guerra ; Eric McDade ; Guoqiao Wang ; Jasmeer P Chhatwal ; Gregory S Day ; Edward Huey ; Mathias Jucker ; Johannes Levin ; Yoshiki Niimi ; James M Noble ; Jee Hoon Roh ; Racquel Sánchez-Valle ; Peter R Schofield ; Randall J Bateman ; Chris Frost ; Nick C Fox ; The Dominantly Inherited Alzheimer Network (DIAN) (2025): Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100133
BRAIN HEALTH PRO/SANTE CERVEAU PRO: THE DEVELOPMENT OF A WEB-BASED PROGRAM FOR DEMENTIA LITERACY AND RISK FACTOR REDUCTION
Sylvie Belleville, Nicole D. Anderson, Louis Bherer, Richard Camicioli, Julie Carrier, Senny Chan, Marc Cuesta, Thien Thanh Dang-Vu, Emily Dwosh, Alexandra J. Fiocco, Guylaine Ferland, Brigitte Gilbert, Elaine Harris, Inbal Itzhak, Pamela Jarrett, Mohamed Abdelhafid Kadri, Danielle Laurin, Teresa Liu-Ambrose, Chris A. McGibbon, Laura Middleton, Lesley Miller, Haakon B. Nygaard, Manuel Montero-Odasso, Kelly Murphy, Natalie Phillips, M. Kathleen Pichora-Fuller, Julie M. Robillard, Eric E. Smith, Mark Speechley, Amal Trigui, Walter Wittich, Howard Chertkow, Howard H. Feldman
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BACKGROUND: Online educational programs focused on ways to improve brain health could increase participant literacy, empowerment, and engagement in activities that support personal brain health, potentially reducing dementia risk.
OBJECTIVES: Our goal was to develop an evidence-based online educational program with a focus on risk and protective factors for dementia. Here we present the rationale and features of the program and include results from a pilot study that assessed usability and acceptability.
DESIGN: This project is part of the Can-Thumbs UP (CTU) initiative. An Intervention Mapping Approach framework and co-construction approach was used to develop the online program. A pre-post pilot open label design was used to test the usability and acceptance of this at-home educational program.
SETTING: The program and assessment for the pilot study were delivered fully remotely.
PARTICIPANTS: Twenty community-dwelling older adults (60–83 years of age, 65 % female) living in Canada who were at increased risk of dementia.
PROGRAM: The Brain Health PRO/Santé Cerveau PRO is a web-based 45-week program available in French and English. It provides general information and guidance on seven modifiable risk factors for dementia: physical activity, nutrition, cognitively stimulating activities, sleep, social and psychological health, vascular health, and vision/hearing. After completing a brief intake questionnaire, users are provided with an individualized risk profile to personalize priorities and goals. During the course of the program, users receive feedback on lifestyle changes. For this pilot study, participants completed a 15-week version of the program.
MEASUREMENTS: This pilot study reports measures of usability (System Usability Scale), acceptance (Technology Acceptance Model-2) as well as risk profiles at intake based on self-reported questionnaires.
RESULTS: Two logic models were developed to identify the determinants of risk for dementia and how these could be targeted by the program. A review of dementia risk and protective factors and online educational programs for older adults, as well as co-creation activities with experts, stakeholders, and citizen advisors, were used to identify the determinants, target, format, and content of the program. The pilot study reports excellent usability and acceptance with scores of 80.4/100 and 93.5/120 respectively.
CONCLUSION: Intervention mapping and co-construction approaches facilitated the design of a program that effectively balances the delivery of scientific content with the specific constraints, needs and abilities of older adults.
CITATION:
Sylvie Belleville ; Nicole D. Anderson ; Louis Bherer ; Richard Camicioli ; Julie Carrier ; Senny Chan ; Marc Cuesta ; Thien Thanh Dang-Vu ; Emily Dwosh ; Alexandra J. Fiocco ; Guylaine Ferland ; Brigitte Gilbert ; Elaine Harris ; Inbal Itzhak ; Pamela Jarrett ; Mohamed Abdelhafid Kadri ; Danielle Laurin ; Teresa Liu-Ambrose ; Chris A. McGibbon ; Laura Middleton ; Lesley Miller ; Haakon B. Nygaard ; Manuel Montero-Odasso ; Kelly Murphy ; Natalie Phillips ; M. Kathleen Pichora-Fuller ; Julie M. Robillard ; Eric E. Smith ; Mark Speechley ; Amal Trigui ; Walter Wittich ; Howard Chertkow ; Howard H. Feldman ; the CTU expert group for the Canadian Consortium on Neurodegeneration in Aging (CCNA), CAN-THUMBS UP Study Group (2025): Brain health PRO/Santé cerveau PRO: The development of a web-based program for dementia literacy and risk factor reduction. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100134
PATIENT MANAGEMENT PATHWAYS IN DEMENTIA – RESOURCE UTILISATION, DIAGNOSIS AND DRUG TREATMENT IN THE STOCKHOLM REGION, SWEDEN
Emil Aho, Dorota Religa, Mozhu Ding, Bengt Winblad, Linus Jönsson, Karin Modig
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BACKGROUND: New diagnostic and therapeutic options for Alzheimer's disease are beginning to be introduced and expected igto become more widely available in the coming years. Improved understanding of current pathways in diagnosis and initial care of patients with dementia can help inform choices around how best to integrate new technologies in existing care structures.
OBJECTIVES: The aim of this study is to describe the care management pathways defined by the involvement of specialist and primary care for individuals with newly diagnosed dementia. It also seeks to characterise individuals in different management pathways based on resource use prior to diagnosis, the type of dementia diagnosis received, and the proportion who receive symptomatic anti-dementia drug treatment.
DESIGN: Observational cohort study.
SETTING: Stockholm region, Sweden.
PARTICIPANTS: All newly diagnosed dementia cases between 1st January 2018 to 30th June 2020 (n = 9,781). Dementia diagnoses in primary care were based on Regional Stockholm health care database and diagnoses in specialist care were based on the National Patient Register in Sweden.
MEASUREMENTS: Care management pathways were categorized into three groups: primary care only (diagnosed and followed up in primary care), specialist, no follow-up (diagnosed in specialist care but not followed up in specialist care), and specialist with follow-up (diagnosed and followed up in specialist care). These classifications were based on patients’ care episodes from the date of diagnosis and the subsequent 18 months. age at diagnosis, resource utilisation one-year prior diagnosis and diagnosis given and symptomatic anti-dementia treatment 18 months after initial diagnosis.
RESULTS: A total of 9,781 newly diagnosed dementia cases were identified. In the 18 months following diagnosis, 63 % of patients were diagnosed either partly or fully in specialist care, while 37 % were diagnosed solely in primary care. Patients diagnosed and managed only in primary care were older, spent more days in hospital, and received more social care in the year preceding their diagnosis. Their total care costs were also the highest. Alzheimer's disease was the most common diagnosis (48 %), while 27 % had an unspecified dementia diagnosis, varying by care setting (61 % for patients managed in primary care only and 6 % for patients diagnosed and followed up in specialist care). Overall, 47 % of patients received symptomatic anti-dementia treatment, with the highest share for patients diagnosed and followed up in specialist care (73 %) and the lowest in primary care only (19 %). Diagnosis varied by age and care setting Alzheimer's was most common in settings involving specialist care, whereas unspecified dementia was more common in primary care only regardless of age.
CONCLUSION: The findings that patients managed exclusively in primary care were older, had higher pre-diagnosis resource utilisation, and were less likely to receive specific diagnoses or anti-dementia treatments highlight the crucial role of primary care in diagnosing and managing dementia among older individuals with complex needs. Further research is needed to explore primary care's role in diagnosis and treatment across diverse healthcare systems.
Future research is needed to explore whether and how new diagnostic tools and treatment for AD could facilitate timely diagnosis and care for older individuals with dementia in primary care.
CITATION:
Emil Aho ; Dorota Religa ; Mozhu Ding ; Bengt Winblad ; Linus Jönsson ; Karin Modig (2025): Patient management pathways in dementia – Resource utilisation, diagnosis and drug treatment in the Stockholm region, Sweden. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100132
MULTI-OMICS ANALYSIS OF DRUGGABLE GENES TO FACILITATE ALZHEIMER\'S DISEASE THERAPY: A MULTI-COHORT MACHINE LEARNING STUDY
Jichang Hu, Yong Luo, Xiaochuan Wang
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BACKGROUND: The swift rise in the prevalence of Alzheimer's disease (AD) alongside its significant societal and economic impact has created a pressing demand for effective interventions and treatments. However, there are no available treatments that can modify the progression of the disease.
METHODS: Eight AD brain tissues datasets and three blood datasets were obtained. Consensus clustering was utilized as a method to discern the various subtypes of AD. Then, module genes were screened using weighted correlation network analysis (WGCNA). Furthermore, screening hub genes was conducted through machine-learning analyses. Finally, A comprehensive analysis using a systematic approach to druggable genome-wide Mendelian randomization (MR) was conducted.
RESULTS: Two AD subclasses were identified, namely cluster.A and cluster.B. The levels of gamma secretase activity, beta secretase activity, and amyloid-beta 42 were found to be significantly elevated in patients classified within cluster A when compared to those in cluster B. Furthermore, by utilizing the differentially expressed genes shared among these clusters, along with identifying druggable genes and applying WGCNA to these subtypes, we were able to develop a scoring system referred to as DG.score. This scoring system has demonstrated remarkable predictive capability for AD when evaluated against multiple datasets. Besides, A total of 30 distinct genes that may serve as potential drug targets for AD were identified across at least one of the datasets investigated, whether derived from brain samples or blood analyses. Among the identified genes, three specific candidates that are considered druggable (LIMK2, MAPK8, and NDUFV2) demonstrated significant expression levels in both blood and brain tissues. Furthermore, our research also revealed a potential association between the levels of LIMK2 and concentrations of CSF Aβ (OR 1.526 (1.155–2.018)), CSF p-tau (OR 1.106 (1.024–01.196)), and hippocampal size (OR 0.831 (0.702–0.948)).
CONCLUSIONS: This study provides a notable advancement to the existing literature by offering genetic evidence that underscores the potential therapeutic advantages of focusing on the druggable gene LIMK2 in the treatment of AD. This insight not only contributes to our understanding of AD but also guides future drug discovery efforts.
CITATION:
Jichang Hu ; Yong Luo ; Xiaochuan Wang (2025): Multi-omics analysis of druggable genes to facilitate Alzheimer's disease therapy: A multi-cohort machine learning study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100128
DIETARY PATTERNS AND BLOOD-BASED BIOMARKERS OF ALZHEIMER\'S DISEASE IN COGNITIVELY INTACT OLDER ADULTS: FINDINGS FROM A POPULATION-BASED STUDY
Anja Mrhar, Adrián Carballo-Casla, Giulia Grande, Martina Valletta, Claudia Fredolini, Laura Fratiglioni, Milica Gregori? Kramberger, Aleš Kuhar, Bengt Winblad, Amaia Calderón-Larrañaga, Davide Liborio Vetrano
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BACKGROUND: Diet can impact cognitive aging, but comprehensive data from human studies is lacking and the underlying biological mechanisms are still not fully understood.
OBJECTIVES: To investigate the associations between two dietary patterns consistently linked to inflammation and brain health [the Mediterranean diet (MDS) and inflammatory potential of diet (EDII)] and five blood-based biomarkers of Alzheimer´s disease (AD) in a sample of dementia-free community-dwelling older adults.
DESIGN AND SETTING: We used cross-sectional data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K).
PARTICIPANTS: Participants who were institutionalized, had dementia or Parkinson's disease, or had missing data on diet and/or biomarkers were excluded. Our study sample consisted of 1907 adults ≥60 years old.
MEASUREMENTS: Adherence to the MDS and EDII was assessed using a validated food frequency questionnaire. T-tau, p-tau181, Aβ 42/40, NfL, and GFAP were measured in serum. Associations were estimated through quantile regression models at the 25th, 50th, and 75th percentiles of the biomarkers’ levels, and were adjusted for potential confounders and stratified by sex, age, and APOE-e4 genotype.
RESULTS: In the whole sample, higher adherence to the MDS was associated with lower levels of p-tau181 at the 50th and 75th percentiles [β (95% CI) per 1-SD increment = -0.028 (-0.053, -0.002) and -0.036 (-0.072, -0.001), respectively], while higher adherence to the EDII was associated with higher levels of NfL at the 75th percentile [β (95% CI) per 1-SD increment =0.031 (0.008, 0.053)]. Associations with other biomarkers were only apparent at lower levels of their distribution. Subgroup analyses showed: 1) a stronger inverse association between the MDS and p-tau181 in APOE-e4 carriers than non-carriers, and 2) an inverse association of the MDS with GFAP only in participants ≥78 years.
CONCLUSIONS: Diet seems to be associated with biomarkers of AD pathology in cognitively intact older adults. Some associations were more apparent in the presence of genetic predisposition for AD or advanced age.
CITATION:
Anja Mrhar ; Adrián Carballo-Casla ; Giulia Grande ; Martina Valletta ; Claudia Fredolini ; Laura Fratiglioni ; Milica Gregorič Kramberger ; Aleš Kuhar ; Bengt Winblad ; Amaia Calderón-Larrañaga ; Davide Liborio Vetrano (2025): Dietary patterns and blood-based biomarkers of Alzheimer's disease in cognitively intact older adults: Findings from a population-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100124
OPPOSITE CAUSAL EFFECTS OF TYPE 2 DIABETES AND METFORMIN ON ALZHEIMER\'S DISEASE
Dongming Liu, Hongbao Cao, Ancha Baranova, Chenxin Xu, Fuquan Zhang
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BACKGROUND: Type 2 diabetes (T2D) is commonly co-morbid with Alzheimer's disease (AD). However, it remains unclear whether T2D itself or the antidiabetic drug metformin contributes to the progression of AD.
OBJECTIVE: This study aimed to investigate the overall and independent effects of T2D and metformin use on the risk of AD.
METHODS: Summary genome-wide association study datasets were utilized for the Mendelian randomization (MR) and multivariable MR (MVMR) analyses, including ones for T2D (N = 455,017), metformin (N = 456,276), and AD (N = 453,733). Additionally, using the proportional imbalance method, we analyzed AD-related adverse drug events in the FDA Adverse Event Reporting System (FAERS) database (covering Q1 2004 to Q2 2024).
RESULTS: Our two-sample MR analysis indicated that T2D is not associated with the risk of AD (OR: 1.03, CI: 0.99–1.08, P = 0.128). However, while not statistically significant, genetic signature for metformin exposure demonstrated a trend toward an increased risk of AD (OR: 1.05, CI: 1.00–1.09, P = 0.053). Interestingly, in MVMR analysis, which evaluates independent effects of T2D and metformin exposure on T2D, we found a robust association of T2D with a decrease in the risk of AD (OR: 0.82, CI: 0.68–0.98, P = 0.031), while the use of metformin was associated with a higher risk of AD (OR: 1.26, CI: 1.06–1.50, P = 9.45E-3). In the FAERS database, a total of 228,283 metformin-related adverse event reports from 67,742 cases were found. For metformin as the target drug and AD as the target adverse event, signal analysis reported 29 cases of AD (ROR: 0.83, 95 % CI: 0.58–1.19, P = 0.3126).
CONCLUSIONS: Our study reveals the opposite independent causal effects of T2D and metformin exposure on AD. These findings highlight the importance of assessing AD risk when prescribing metformin to patients with T2D.
CITATION:
Dongming Liu ; Hongbao Cao ; Ancha Baranova ; Chenxin Xu ; Fuquan Zhang (2025): Opposite causal effects of type 2 diabetes and metformin on Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100129
LONGITUDINAL ASSOCIATIONS OF CAROTID ARTERY STIFFNESS WITH PROGRESSION OF CEREBROVASCULAR DISEASE, INCIDENT DEMENTIA AND COGNITIVE DECLINE IN OLDER ADULTS
Caroline Robert, Lieng-Hsi Ling, Eugene S.J. Tan, Narayanaswamy Venketasubramanian, Shir Lynn Lim, Lingli Gong, Josephine Lunaria Berboso, Arthur Mark Richards, Christopher Chen, Saima Hilal, Josephine Lunaria Berboso, Arthur Mark Richards, Christopher Chen, Saima Hilal
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BACKGROUND: Carotid artery stiffness is associated with cerebrovascular disease (CeVD) and cognitive impairment, but evidence for its longitudinal effects on progression of CeVD and cognitive decline are limited.
OBJECTIVES: To evaluate the longitudinal associations of carotid artery stiffness with CeVD progression, incident dementia, and cognitive decline.
DESIGN: Longitudinal analyses from a memory-clinic cohort with a follow-up of 2 years.
SETTING: A memory-clinic study.
PARTICIPANTS: 194 participants (mean age=80, 63 % female) with or without cognitive impairments provided consent to take part in the study.
MEASUREMENTS: Participants underwent carotid ultrasonography, brain MRI, and neuropsychological assessments were at baseline and follow-up. Carotid stiffness measures included ß-index, elastic modulus (Ep), and pulse wave velocity-ß (PWV-ß). CeVD markers included white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs) and cortical infarcts. Cognition was assessed with a neuropsychological battery.
RESULTS: After 2 years, incident CeVD cases included lacunes (15.7 %), CMBs (23.8 %), and cortical infarcts (7.6 %). ß-index (ß=0.78, p < 0.001), Ep (ß=0.94, p < 0.001), and PWV-ß (ß=0.15, p = 0.003) were independently associated with WMH progression. Ep (ß=-0.15, p = 0.007) and PWV-ß (ß=-3.68, p = 0.007) were independently associated with visuomotor speed decline. No association was found with incident lacunes, CMBs or dementia.
CONCLUSION: Carotid stiffness progression is associated with WMH progression and visuomotor speed decline.
CITATION:
Caroline Robert ; Lieng-Hsi Ling ; Eugene S.J. Tan ; Narayanaswamy Venketasubramanian ; Shir Lynn Lim ; Lingli Gong ; Josephine Lunaria Berboso ; Arthur Mark Richards ; Christopher Chen ; Saima Hilal (2025): Longitudinal associations of carotid artery stiffness with progression of cerebrovascular disease, incident dementia and cognitive decline in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100127
JPAD Volume 12, N°05 - 2025
EDITORIAL: ARE APPROPRIATE USE RECOMMENDATIONS USEFUL IN CLINICAL PRACTICE?
Serge Gauthier
J Prev Alz Dis 2025;5(12)
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CITATION:
Serge Gauthier (2025): Are Appropriate Use Recommendations useful in clinical practice?. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100165
DONANEMAB: APPROPRIATE USE RECOMMENDATIONS
G.D. Rabinovici, D.J. Selkoe, S.E. Schindler, P. Aisen, L.G. Apostolova, A. Atri, S.M. Greenberg, S.B. Hendrix, R.C. Petersen, M. Weiner, S. Salloway, J. Cummings
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryDonanemab (Kisunla®), an IgG1 monoclonal antibody targeting N-terminal pyroglutamate-modified forms of amyloid-β, is approved in the United States for treatment of early symptomatic Alzheimer's disease (AD). Appropriate Use Recommendations (AUR) were developed to guide the implementation of donanemab in real-world practice, prioritizing safety considerations and opportunity for effectiveness. The AUR were developed by the AD and Related Disorders Therapeutic Workgroup by consensus, integrating available data and expert opinion. Appropriate candidates for donanemab treatment include persons with mild cognitive impairment or mild dementia due to AD (Clinical Stages 3–4, MMSE 20–30) who have biomarker confirmation of AD pathology by PET or CSF. Tau PET is not required for eligibility. Apolipoprotein E (APOE) genotyping should be performed prior to treatment to inform an individual's risk of developing Amyloid-Related Imaging Abnormalities (ARIA). Pre-treatment MRI should be obtained no more than 12 months prior to treatment. Patients with findings of >4 cerebral microbleeds, cortical superficial siderosis or a major vascular contribution to cognitive impairment should be excluded from treatment. The decision to initiate therapy should be grounded in a shared decision-making process that emphasizes the patient's values and goals of care. Donanemab is administered as a monthly intravenous infusion. Surveillance MRIs to evaluate for ARIA should be performed prior to the 2nd, 3rd, 4th and 7th infusions, prior to the 12th dose in higher risk individuals, and at any time ARIA is suspected clinically. Clinicians may consider discontinuing treatment if amyloid clearance is demonstrated by amyloid PET, typically obtained 12–18 months after initiating treatment.
CITATION:
G.D. Rabinovici ; D.J. Selkoe ; S.E. Schindler ; P. Aisen ; L.G. Apostolova ; A. Atri ; S.M. Greenberg ; S.B. Hendrix ; R.C. Petersen ; M. Weiner ; S. Salloway ; J. Cummings (2025): Donanemab: Appropriate use recommendations. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100150
DISTINCT TRAJECTORIES OF SUBJECTIVE COGNITIVE DECLINE BEFORE DIAGNOSIS OF NEUROCOGNITIVE DISORDERS: LONGITUDINAL MODELLING OVER 18 YEARS
Tau Ming Liew, Tau Ming Liew
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Subjective cognitive decline (SCD) is an established predictor of neurocognitive disorders (NCD) (i.e. mild cognitive impairment and dementia). Yet, its construct remains contentious. Many individuals with SCD do not progress to NCD, leading to an alternative term in the literature – ‘functional cognitive disorders’ – to describe the SCD experience in these individuals.
OBJECTIVES: To examine the distinct differences in trajectories of SCD between those who did and did not eventually develop NCD.
DESIGN: Case-control study.
SETTING: Alzheimer's Disease Centers across USA.
PARTICIPANTS: A total of 5,167 participants aged ≥50 years were followed up near-annually to evaluate for SCD and NCD (median follow-up=8.1 years; range=1.0–18.0). Cases were defined as those who developed incident NCD during follow-up; controls completed ≥10 years of follow-up and had normal cognition throughout follow-up period.
MEASUREMENTS: SCD was evaluated with a yes/no question based on “perceived decline in memory relative to previously attained abilities”. The trajectories of SCD were modelled with mixed-effect logistic regression, using a backward timescale.
RESULTS: Those who developed NCD (cases) had new onset of SCD within past 20 years, which became particularly noticeable 13–14 years before diagnosis, and became even more evident in the last 4 years. Those who did not develop NCD (controls) reported SCD since younger age, with the probability of SCD remaining constant over time. The distinctive trajectories were consistent across Alzheimer's and non-Alzheimer's disease, and among those with higher baseline rates of SCD due to psychiatric conditions.
CONCLUSIONS: SCD exhibits distinctive trajectories among those who do and do not progress to NCD. These distinctive trajectories can inform NCD risk for early interventions, and guide public health messaging to distinguish high-risk SCD from normal ageing. Future SCD scales may possibly need to evaluate symptom changes over a longer, 20-year horizon to better capture the new onset of SCD within this longer timeframe.
CITATION:
Tau Ming Liew (2025): Distinct trajectories of subjective cognitive decline before diagnosis of neurocognitive disorders: Longitudinal modelling over 18 years. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100123
CLARITY AD: ASIAN REGIONAL ANALYSIS OF A PHASE III TRIAL OF LECANEMAB IN EARLY ALZHEIMER\'S DISEASE
Christopher Chen, Sadao Katayama, Jae-Hong Lee, Jun-Young Lee, Masaki Nakagawa, Kentaro Torii, Tomoo Ogawa, Amitabh Dash, Michael Irizarry, Shobha Dhadda, Michio Kanekiyo, Steve Hersch, Takeshi Iwatsubo
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Across Asia, Alzheimer's disease prevalence is expected to rise dramatically due to, among other factors, rapidly aging populations. Alzheimer's disease pathology is triggered by the accumulation of soluble and insoluble aggregated Aβ peptides (oligomers, protofibrils, and fibrils). Lecanemab is a recently approved humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils), with activity at insoluble fibrils. In the recent 18-month phase 3 Clarity AD study, lecanemab demonstrated a consistent slowing of decline in clinical (global, cognitive, functional, and quality of life) outcomes, and reduction in brain amyloid in early Alzheimer's disease. Lecanemab was well tolerated in Clarity AD, with an increase in incidence of infusion related reactions and amyloid-related imaging abnormalities (ARIA) versus placebo.
OBJECTIVES: The objective of this manuscript is to present the results for the Asian region population of Clarity AD.
DESIGN: The core Clarity AD study was an 18-month, multicenter, double-blind, placebo-controlled, parallel-group study.
SETTING: Academic and clinical centers in Asia.
PARTICIPANTS: A total of 294 individuals with early Alzheimer's disease (i.e., mild cognitive impairment or mild Alzheimer's disease).
INTERVENTION: Eligible patients were randomized across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly) according to a fixed 1:1 schedule.
MEASUREMENTS: The primary efficacy endpoint in the core study was change in the Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) from baseline at 18 months. Key secondary endpoints included change from baseline at 18 months in amyloid PET Centiloids (in patients participating in the amyloid PET sub-study), AD COMposite Score (ADCOMS) and AD Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14). Safety was monitored throughout the study in a blinded manner by the sponsor and in an unblinded manner by an independent data safety monitoring committee.
RESULTS: Of the total of 1795 subjects randomized in Clarity AD, 294 subjects were in the Asian region (Japan:152; Korea:129; Singapore:13). The efficacy of lecanemab was consistent with the overall population. For the primary endpoint, there was a slowing of decline with lecanemab in the CDR-SB at 18 months compared to placebo in the Asian region (adjusted mean difference: -0.349; 95 % confidence intervals: -0.773, 0.076; 24 % slowing of decline). Results for the secondary efficacy endpoints also favored lecanemab versus placebo in Asians. Lecanemab was well tolerated in Asian subjects, with a safety profile in Asian subjects similar to the overall Clarity AD population. The most common adverse events of special interest were ARIA-H (lecanemab:14.4 %; placebo:16.2 %), ARIA-E (lecanemab:6.2 %; placebo:1.4 %), and infusion-related reactions (lecanemab:12.3 %; placebo:1.4 %). Incidence of adverse events leading to study drug dose interruption or withdrawal, infusion-related reactions, ARIA-E and ARIA-H was lower for the lecanemab treated group in the Asian region relative to the overall Clarity AD population. Results from quality of life and biomarker assessments in the Asia region were also generally similar to the overall Clarity AD population.
CONCLUSION: In the Clarity AD Asian region cohort, the overall efficacy, biomarker changes and safety profile of lecanemab were consistent with the overall population, with a favorable risk-benefit profile and manageable risks. ARIA events and infusion-related reactions occurred less commonly with lecanemab in the Asian region subgroup than the overall population.
CITATION:
Christopher Chen ; Sadao Katayama ; Jae-Hong Lee ; Jun-Young Lee ; Masaki Nakagawa ; Kentaro Torii ; Tomoo Ogawa ; Amitabh Dash ; Michael Irizarry ; Shobha Dhadda ; Michio Kanekiyo ; Steve Hersch ; Takeshi Iwatsubo (2025): Clarity AD: Asian regional analysis of a phase III trial of lecanemab in early Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100160
HEALTHY DIETARY PATTERNS IN RELATION TO COGNITIVE PERFORMANCE AND ALZHEIMER\'S DISEASE MORTALITY
Yiying Gong, Hui Chen, Yuxuan Gu, Jie Shen, Ting Shen, Yihong Ding, Mengxi Lu, Liyan Huang, Minqing Yan, Peige Song, Yajie Zhu, Shuang Rong, Changzheng Yuan
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Dietary factors play a major role in cognitive aging, but few studies have assessed and compared the associations between specific dietary patterns and Alzheimer's disease (AD) mortality.
METHODS: We included 27,773 U.S. participants (mean age = 59.8 years, 51.4 % female) from the National Health and Nutrition Examination Survey (NHANES) between 1998 and 2016, with follow-up for AD mortality until December 2019. Five dietary pattern scores were calculated utilizing one (1999–2002) or two repeated (2003–2016) 24hr dietary recalls, including the Healthy Eating Index (HEI-2015), the healthful plant-based diet index (hPDI), the alternate Mediterranean diet (aMED), the Dietary Approach to Stop Hypertension diet (DASH), and the Mediterranean-DASH Intervention for Neurodegeneration Delay diet (MIND) scores. We utilized Cox proportional hazard models to evaluate the associations of these dietary pattern scores with AD mortality.
RESULTS: A total of 260 AD deaths occurred during a median follow-up of 9.8 years. Higher aMED score was associated with a lower risk of AD mortality (HRT3 vs T1: 0.72, 95 % CI, 0.52–1.00, p-trend = 0.041). In a sub-sample of 2,713 participants in NHANES 2011-2014, 432 individuals had prevalent psychometric mild cognitive impairment (p-MCI). Higher aMED, MIND, HEI-2015, and hPDI were associated with lower odds of p-MCI. The potential contributors to these associations included higher intake levels of vegetables and nuts, moderate alcohol consumption, and lower intake level of sweets.
CONCLUSIONS: The Mediterranean dietary pattern was associated with more favorable cognitive outcomes among middle-aged and older adults, underscoring the importance of a healthy diet for long-term benefits in cognitive and brain health.
CITATION:
Yiying Gong ; Hui Chen ; Yuxuan Gu ; Jie Shen ; Ting Shen ; Yihong Ding ; Mengxi Lu ; Liyan Huang ; Minqing Yan ; Peige Song ; Yajie Zhu ; Shuang Rong ; Changzheng Yuan (2025): Healthy dietary patterns in relation to cognitive performance and Alzheimer's disease mortality. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100100
BRAIN HEALTH SERVICES FOR THE SECONDARY PREVENTION OF COGNITIVE IMPAIRMENT AND DEMENTIA: OPPORTUNITIES, CHALLENGES, AND THE BUSINESS CASE FOR EXISTING AND FUTURE FACILITIES
Giovanni B. Frisoni, Federica Ribaldi, Gilles Allali, Théophile Bieth, Andrea Brioschi Guevara, Stefano Cappa, Lisa Cipolotti, Kristian Steen Frederiksen, Jean Georges, Frank Jessen, Giacomo Koch, Hugh Masters, Augusto J. Mendes, Lutz Frölich, Valentina Garibotto, Oriol Grau-Rivera, Federico E. Pozzi, Dorota Religa, Ayda Rostamzadeh, Lenny Shallcross, Susan D. Shenkin, Wiesje M. van der Flier, Meike W. Vernooij, Leonie N.C. Visser, Jeffrey L. Cummings, Philip Scheltens, Bruno Dubois, Elena Moro, Claudio L.A. Bassetti, Miia Kivipelto
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryA European Task Force has recently developed and published the concept and protocols for the setup of the innovative health offer of Brain Health Services for the secondary prevention of dementia and cognitive impairment (dBHS). dBHS are outpatient health care facilities where adult persons can find an assessment of their risk of developing cognitive impairment and dementia, have their risk level and contributing factors communicated using appropriate language supported by adequate communication tools, can decide to participate to programs for personalized risk reduction if at higher risk, and benefit from cognitive enhancement interventions. This health offer is distinct from that of currently active memory clinics. The ultimate aim of dBHS is to extend healthy life, free from cognitive impairment. Here, we (i) discuss the pertinent opportunities and challenges for those persons who want to benefit from dBHS, professionals, and wider society, (ii) describe the concepts, protocols, organizational features, and patient journeys of some currently active dBHS in Europe, and (iii) argue in favor of the business case for dBHS in Europe.
CITATION:
Giovanni B. Frisoni ; Federica Ribaldi ; Gilles Allali ; Théophile Bieth ; Andrea Brioschi Guevara ; Stefano Cappa ; Lisa Cipolotti ; Kristian Steen Frederiksen ; Jean Georges ; Frank Jessen ; Giacomo Koch ; Hugh Masters ; Augusto J. Mendes ; Lutz Frölich ; Valentina Garibotto ; Oriol Grau-Rivera ; Federico E. Pozzi ; Dorota Religa ; Ayda Rostamzadeh ; Lenny Shallcross ; Susan D. Shenkin ; Wiesje M. van der Flier ; Meike W. Vernooij ; Leonie N.C. Visser ; Jeffrey L. Cummings ; Philip Scheltens ; Bruno Dubois ; Elena Moro ; Claudio L.A. Bassetti ; Miia Kivipelto (2025): Brain health services for the secondary prevention of cognitive impairment and dementia: Opportunities, challenges, and the business case for existing and future facilities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100098
CARDIOVASCULAR-KIDNEY-METABOLIC SYNDROME AND INCIDENCE OF DEMENTIA AMONG OLDER ADULTS
Xiaqing Jiang, Amber L. Bahorik, Christina S. Dintica, Kristine Yaffe
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Cardiovascular-Kidney-Metabolic Syndrome (CKM) has profound impacts on cardiovascular events and mortality, yet its association with dementia risk remains poorly understood.
OBJECTIVES: To investigate associations between CKM and dementia risk.
DESIGN: The prospective cohort study is within the Health, Aging, and Body Composition study, which enrolled participants from 1997 to 1998, with a 15-year follow-up for incident dementia.
SETTING: The population-based study took place in two US communities in Memphis, Tennessee, and Pittsburgh, Pennsylvania.
PARTICIPANTS: Of the 3,075 participants aged 70 to 79 years initially enrolled, 14 were excluded for lacking baseline cognitive assessment, 308 for baseline cognitive impairment, 4 for missing follow-up, and 108 for missing CKM data, resulting in 2,641 in the analysis.
MEASUREMENTS: CKM staging, as defined recently by the American Heart Association framework, was based on constructs comprising dysfunctional adiposity, metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease (CVD). Dementia was identified using hospital records, prescriptions for dementia medication, and a test of global cognition. Adjusted Cox and Fine-Gray proportional hazards models were used to estimate dementia risk and account for competing risk of death.
RESULTS: The 2,641 participants had a mean (SD) age of 74 (2.8) years at baseline; 53 % were female, 36 % were of Black race, and had a range of baseline CKM: 3 % Stage 0 (no CKM), 4 % Stage 1 (excess/dysfunctional adiposity), 26 % Stage 2 (metabolic risk factors), 24 % Stage 3 (subclinical CVD and CKD), and 43 % Stage 4 (clinical CVD and CKD). Compared to participants with CKM Stages 0–2, those with CKM Stages 3–4 had a 50 % increase in dementia risk (hazard ratio 1.50, 95 % CI 1.20 to 1.86) in the fully adjusted model. The association remained significant after additional adjustment for metabolic risk factors, CVD, and CKD, both separately and together. Accounting for competing risk of death yielded similar results.
CONCLUSIONS: Among community-dwelling older adults, advanced CKM is associated with an increased risk of dementia. Older adults with CKM may need to be followed closely for adverse cognitive outcomes, and modifiable risk factors should be managed proactively.
CITATION:
Xiaqing Jiang ; Amber L. Bahorik ; Christina S. Dintica ; Kristine Yaffe (2025): Cardiovascular-kidney-metabolic syndrome and incidence of dementia among older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100112
COMPARATIVE EFFICACY AND SAFETY OF ANTIDIABETIC AGENTS IN ALZHEIMER\'S DISEASE: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Zixin Cai, Jiaxin Zhong, Guanghui Zhu, Jingjing Zhang
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Emerging evidence suggests that antidiabetic agents may offer neuroprotective effects by targeting shared pathophysiological mechanisms such as insulin resistance and neuroinflammation. However, the comparative efficacy, and safety of these agents in the treatment of AD remain unclear.
OBJECTIVES: This study aimed to systematically evaluate and compare the efficacy and safety of antidiabetic agents for improving cognitive outcomes, reducing amyloid-β (Aβ) deposition, and managing adverse effects in patients with AD, using a network meta-analysis of randomized controlled trials (RCTs).
METHODS: A comprehensive literature search was conducted across multiple databases to identify RCTs examining the effects of antidiabetic agents in patients with AD. The primary outcomes included cognitive performance (e.g., MMSE scores), Aβ deposition (measured via CSF biomarkers), and safety/adverse effects. A network meta-analysis was performed to integrate direct and indirect evidence, ranking interventions using Surface Under the Cumulative Ranking (SUCRA) probabilities. Risk of bias was assessed using the Cochrane risk-of-bias tool.
RESULTS: A total of 26 studies, involving 7,361 participants, were included in the analysis. The interventions evaluated included insulin detemir (both low-dose and high-dose), liraglutide, exenatide, metformin, and pioglitazone. Both low-dose insulin detemir (mean difference: 2.10, 95 % CI: 1.04 to 3.15), high-dose insulin detemir (mean difference: 1.40, 95 % CI: -0.07 to 2.88), exenatide (mean difference: 1.19, 95 % CI: 0.06 to 2.32), and metformin combined with exenatide (mean difference: 1.06, 95 % CI: -1.68 to 3.80) showed cognitive improvements compared to placebo. Among these, low-dose insulin detemir demonstrated the most significant improvement. In terms of reducing Aβ deposition, metformin ranked highest in effectiveness, with the highest SUCRA score (84.6), followed by high-dose insulin detemir (SUCRA: 54.1). Low-dose insulin detemir (SUCRA: 51.1) also demonstrated moderate efficacy. Low-dose insulin detemir showed some reduction in Aβ deposition (mean difference: -0.31, 95 % CI: -2.82 to 2.20), although statistical significance was limited. Liraglutide exhibited the highest rate of study treatment withdrawal (mean difference: 1.97, 95 % CI: -0.07 to 4.00), while pioglitazone demonstrated the lowest withdrawal rates (mean difference: 0.07, 95 % CI: -0.03 to 0.17).
CONCLUSIONS: This network meta-analysis provides valuable insights into the comparative efficacy and safety of antidiabetic agents in AD. Low-dose insulin detemir demonstrated the most significant cognitive improvement and a moderate effect on reducing Aβ deposition. Metformin emerged as the most effective agent for reducing Aβ levels, though its effects on cognitive function were less pronounced. Safety profiles varied, with liraglutide associated with the highest rate of treatment withdrawals, while pioglitazone demonstrated the lowest incidence of treatment-related discontinuations. These findings support the potential use of antidiabetic agents, particularly insulin detemir, as a therapeutic option for AD, although further studies are needed to confirm their long-term benefits and safety.
CITATION:
Zixin Cai ; Jiaxin Zhong ; Guanghui Zhu ; Jingjing Zhang (2025): Comparative efficacy and safety of antidiabetic agents in Alzheimer's disease: A network meta-analysis of randomized controlled trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100111
ASSOCIATION OF DIETARY FATTY ACIDS WITH LONGITUDINAL CHANGE IN PLASMA-BASED BIOMARKERS OF ALZHEIMER\'S DISEASE
Serena S. Hoost, Lawrence S. Honig, Min Suk Kang, Aanya Bahl, Annie J. Lee, Danurys Sanchez, Dolly Reyes-Dumeyer, Rafael A. Lantigua, Jeffrey L. Dage, Adam M. Brickman, Jennifer J. Manly, Richard Mayeux, Yian Gu
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Elevated intake of omega-3 polyunsaturated fatty acids is linked to a reduced risk of dementia in some prospective studies. However, few studies have examined the relationship between nutrient intake and plasma biomarkers of Alzheimer's disease.
OBJECTIVES: We explored whether omega-3, omega-6, and monounsaturated fat intakes were associated with changes in plasma biomarkers of Alzheimer's disease over time.
DESIGN: The Washington Heights-Inwood Columbia Aging Project is a prospective cohort study (1994–2021); the data set used here includes a mean follow-up of 7.0 years.
SETTING: Community-based in New York City.
PARTICIPANTS: 599 dementia-free individuals at baseline who completed a 61-item food frequency questionnaire and had biomarkers measured in plasma from at least two different time points.
MEASUREMENTS: Fatty acid intake tertiles were computed from participant-completed 61-item Willett semi-quantitative food frequency questionnaires (Channing Laboratory, Cambridge, Massachusetts) obtained once at their baseline visit. Plasma-based biomarker assays were performed, using the single molecule array technology Quanterix Simoa HD-X platform, at baseline and follow-up visits. Generalized Estimating Equations (GEE) models were used to evaluate the association between baseline nutrient intake tertile and changes in biomarkers including phospho-tau181, amyloid-beta 42/40 ratio, phospho-tau181/amyloid-beta42 ratio, glial fibrillary acidic protein, neurofilament light chain, and two biomarker patterns derived from Principal Component Analysis (PCA1 and PCA2), with higher scores indicating a high level of neurodegeneration and low level of Alzheimer's disease burden, respectively). Models were adjusted for age, sex, race/ethnicity, education, and calculated total energy intake initially, and additionally for cerebrovascular risk factors.
RESULTS: Higher baseline omega-3 intake tertile was associated with lesser decline in PCA2 (β = 0.221, p < 0.001) and amyloid-beta 42/40 ratio (β = 0.022, p = 0.003), and a lesser rise in phospho-tau181 (β = -0.037, p = 0.001). Higher omega-6 intake tertile was linked to a lesser rise in phospho-tau181 (β = -0.050, p < 0.001) and glial fibrillary acidic protein (β = -0.028, p = 0.002). Most associations persisted after adjusting for cardiovascular risk factors.
CONCLUSIONS: Higher relative baseline intake of omega-3 and omega-6 fatty acids is associated with lesser progression of blood-based biomarkers of Alzheimer's disease. Consuming healthy fatty acids may help prevent accumulation of Alzheimer's disease-related pathological changes.
CITATION:
Serena S. Hoost ; Lawrence S. Honig ; Min Suk Kang ; Aanya Bahl ; Annie J. Lee ; Danurys Sanchez ; Dolly Reyes-Dumeyer ; Rafael A. Lantigua ; Jeffrey L. Dage ; Adam M. Brickman ; Jennifer J. Manly ; Richard Mayeux ; Yian Gu (2025): Association of dietary fatty acids with longitudinal change in plasma-based biomarkers of Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100117
FEASIBILITY AND ACCEPTABILITY OF REMOTE APOE-GENOTYPING AMONG RESEARCH VOLUNTEERS OF AN ONLINE RECRUITMENT REGISTRY (THE DUTCH BRAIN RESEARCH REGISTRY)
L. Waterink, S.J. van der Lee, D. Nijland, F.I. van der Zee, L.N.C. Visser, Y.A.L. Pijnenburg, S.A.M. Sikkes, W.M. van der Flier, M.D. Zwan
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Participant recruitment for preclinical Alzheimer's disease (AD) prevention studies is challenging. Online registries facilitate large scale prescreening of individuals at risk for AD to accelerate recruitment. APOE-prescreening has the potential to better identify at-risk individuals. This study investigated the feasibility and acceptability of at-home APOE-genotyping in cognitively-normal registrants of an online registry.
METHODS: We invited 9,287 cognitively-normal registrants of Dutch Brain Research Registry (DBRR) aged 50 to 75 for at-home APOE-genotype testing, without receiving the results. Feasibility was measured by participation ratio (participation/interested), swab-return ratio (returned-swabs/participation), and genotyping-success ratio (analyzed swabs/returned swabs). Acceptability was measured with online questions about information provision and project scope. We explored prescreening questions potentially reducing screen-failures.
RESULTS: Feasibility was high with an 0.89 participation ratio (2,886/3,251), 0.90 swab-return ratio (2,886/2,597), 0.99 genotyping-success ratio (2,558/2,597). Acceptability was high, as participants were content with the information provision (87 %-97 %, n = 1,709–1,894), which was also well understood (91 %-93 %, n = 1,772–1,802). Among successful-analyzed swabs (n = 2,558), 27 % participants were APOE-ε4 heterozygote (n = 703), and 2 % homozygote (n = 60). Prescreening on a positive family history leads to a third reduction in the number of invitations needed to identify one APOE-ε4 carrier.
CONCLUSION: Our results suggest that APOE-ɛ4 genotyping in participants of an online research registry is feasible, well received and could be used to prescreen individuals at risk for AD for prevention studies. Adding a positive family history before invitation for APOE-genotyping, would further improve the prescreening process and reduce screen failures when identifying carriers.
CITATION:
L. Waterink ; S.J. van der Lee ; D. Nijland ; F.I. van der Zee ; L.N.C. Visser ; Y.A.L. Pijnenburg ; S.A.M. Sikkes ; W.M. van der Flier ; M.D. Zwan ; (2025): Feasibility and acceptability of remote APOE-genotyping among research volunteers of an online recruitment registry (The Dutch Brain Research Registry). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100099
MACHINE LEARNING TO DETECT ALZHEIMER\'S DISEASE WITH DATA ON DRUGS AND DIAGNOSES
Johanna Wallensten, Caroline Wachtler, Nenad Bogdanovic, Anna Olofsson, Miia Kivipelto, Linus Jönsson, Predrag Petrovic, Axel C. Carlsson
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Integrating machine learning with medical records offers potential for early detection of Alzheimer's disease (AD), enabling timely interventions.
OBJECTIVES: This study aimed to evaluate the effectiveness of machine learning in constructing a predictive model for AD, designed to predict AD with data up to three years before diagnosis. Using clinical data, including prior diagnoses and medical treatments, we sought to enhance sensitivity and specificity in diagnostic procedures. A second aim was to identify the most important factors in the machine learning models, as these may be important predictors of AD.
DESIGN: The study employed Stochastic Gradient Boosting, a machine learning method, to identify diagnoses predictive of AD using primary healthcare data. The analyses were stratified by sex and age groups.
SETTING: The study included individuals within Region Stockholm, Sweden, using medical records from 2010 to 2022.
PARTICIPANTS: The study analyzed clinical data for individuals over the age of 40. Patients with an AD diagnosis (ICD-10-SE codes F00 or G30) during 2010–2012 were excluded to ensure prospective modeling. In total, AD was identified in 3,407 patients aged 41–69 years and 25,796 patients aged over 69.
MEASUREMENTS: The machine learning model ranked predictive diagnoses, with performance assessed by the area under the receiver operating characteristic curve (AUC). Known and novel predictors were evaluated for their contribution to AD risk.
RESULTS: AUC values ranged from 0.748 (women aged 41–69) to 0.816 (women over 69), with men across age groups falling within this range.
Sensitivity and specificity ranged from 0.73 to 0.79 and 0.66 to 0.79, respectively, across age and gender groups. Negative predictive values were consistently high (≥0.954), while positive predictive values were lower (0.199–0.351).
Additionally, we confirmed known risk factors as predictors and identified novel predictors that warrant further investigation. Key predictors included medical observations, cognitive symptoms, antidepressant treatment, visit frequency, and vitamin B12/folic acid treatment.
CONCLUSIONS: Machine learning applied to clinical data shows promise in predicting AD, with robust model performance across age and sex groups. The findings confirmed known risk factors, such as depression and vitamin B12 deficiency, while also identifying novel predictors that may guide future research. Clinically, this approach could enhance early detection and risk stratification, facilitating timely interventions and improving patient outcomes.
CITATION:
Johanna Wallensten ; Caroline Wachtler ; Nenad Bogdanovic ; Anna Olofsson ; Miia Kivipelto ; Linus Jönsson ; Predrag Petrovic ; Axel C. Carlsson (2025): Machine learning to detect Alzheimer's disease with data on drugs and diagnoses. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100115
THE ASSOCIATIONS BETWEEN FRESH VEGETABLE AND FRUIT CONSUMPTION AND PLASMA AND PET BIOMARKERS IN PRECLINICAL ALZHEIMER\'S DISEASE: A CROSS-SECTIONAL AND LONGITUDINAL STUDY OF CHINESE POPULATION
Heling Chu, Chuyi Huang, Fang Xie, Qihao Guo
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: The identification of the modifiable lifestyle factors including dietary habits in older adults of preclinical Alzheimer's disease (AD) and early effective interventions are of great importance.
OBJECTIVES: We studied whether the consumption of fresh vegetables and fruits was different between cognitively unimpaired (CU) and cognitively impaired (CI) population and mainly investigated the associations between vegetable and fruit consumption and PET and plasma AD biomarkers in older CU adults with higher β-amyloid (Aβ) burden.
DESIGN, SETTING, AND PARTICIPANTS: Older adults with the age of 50–85 years were enrolled for a cross-sectional and longitudinal study. The groups depended on whether the participants were CU or CI. Partial participants whose habits remained unchanged were followed up.
MEASUREMENTS: The consumption data of vegetables and fruits were collected using a validated self-reported questionnaire. We mainly investigated the associations between vegetable and fruit consumption and various biomarkers in CU participants with positive 18F-florbetapir PET scan (Aβ-PET), part of whom also underwent plasma AD biomarkers tests and 18F-MK6240 PET scan (tau-PET). Correlation and multiple linear regression analyses were used to investigate the associations between vegetable and fruit consumption and AD biomarkers.
RESULTS: A total of 1433 participants were enrolled, of which CU accounted for 49.4 %. Most of the intake habits of vegetables and fruits was different between CU and CI participants. 177 CU participants with Aβ-PET positive were selected for the following study. Multiple linear regression analysis showed higher consumption of fresh vegetables (>200 g/d), dark vegetables (>100 g/d, ≥2d/week), fruits (>100 g/d), berries (>100 g/d) and grapes (>100 g/d) more or less had associations with the plasma biomarkers including Aβ40, t-Tau, p-Tau-181 and neurofilament light chain as well as amyloid and Tau PET biomarkers. Most of the habits were associated with the change of cognitive function after an approximately two-year follow-up. Especially, higher intakes of fruits and grapes correlated with both lower Aβ and Tau burden and inversely with cognitive decline after follow-up.
CONCLUSION: Our data indicates that higher consumption of vegetables, dark vegetables, fruits, berries and grapes is associated with amyloid and Tau PET and plasma biomarkers in preclinical AD participants and the changes of cognitive function after follow-up. Higher intakes of fruits (>100 g/d) and grapes (>100 g/d) may be more helpful for reducing the risk of AD development.
CITATION:
Heling Chu ; Chuyi Huang ; Fang Xie ; Qihao Guo (2025): The associations between fresh vegetable and fruit consumption and plasma and PET biomarkers in preclinical Alzheimer's disease: A cross-sectional and longitudinal study of Chinese population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100076
PREDICTING COGNITIVE DECLINE: DEEP-LEARNING REVEALS SUBTLE BRAIN CHANGES IN PRE-MCI STAGE
Ling Yue, Yongsheng Pan, Wei Li, Junyan Mao, Bo Hong, Zhen Gu, Mingxia Liu, Dinggang Shen, Shifu Xiao
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Mild cognitive impairment (MCI) and preclinical MCI (e.g., subjective cognitive decline, SCD) are considered risk states of dementia, such as Alzheimer's Disease (AD). However, it is challenging to accurately predict conversion from normal cognition (NC) to MCI, which is important for early detection and intervention. Since neuropathological changes may have occurred in the brain many years before clinical AD, we sought to detect the subtle brain changes in the pre-MCI stage using a deep-learning method based on structural Magnetic Resonance Imaging (MRI).
OBJECTIVES: To discover early structural neuroimaging changes that differentiate between stable and progressive cognitive status, and to establish a predictive model for MCI conversion.
DESIGN, SETTING AND PARTICIPANTS: We first created a unique deep-learning framework for pre-AD conversion prediction through the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1) database (n = 845). Then, we tested the model on ADNI-2 (n = 321, followed 3 years) and our private study (n = 109), the China Longitudinal Aging Study (CLAS), to validate the rationality for pre-MCI conversion prediction. The CLAS is a 7-year community-based cohort study in Shanghai. Our framework consisted of two steps: 1) a single-ROI-based network (SRNet) for identifying informative regions in the brain, and 2) a multi-ROI-based network (MRNet) for pre-AD conversion prediction. We then utilized these "ROI-based deep learning" neural networks to create a composite score using advanced algorithm-building. We coined this score as the Progressive Index (PI), which serves as a metric for assessing the propensity of AD conversion. Ultimately, we employed the PI to gauge its predictive capability for MCI conversion in both ADNI-2 and CLAS datasets.
MEASUREMENTS: We primarily utilized baseline T1-weighted MRI scans to identify the most discriminative brain regions and subsequently developed the PI in both training and validation datasets. We compared the PI across different cognitive groups and conducted logistic regression models along with their AUCs, adjusting for education level, gender, neuropsychological test scores, and the presence of comorbid conditions.
RESULTS: We trained the SRNet and MRNet using 845 subjects from ADNI-1 with baseline MRI data, in which AD and progressive MCI (converting to AD within 3 years) patients were considered as positive samples, while NC and stable MCI (remaining stable for 3 years) subjects were considered as negative samples. The convolutional neural networks identified the top 10 regions of interest (ROIs) for distinguishing progressive from stable cases. These key brain regions included the hippocampus, amygdala, temporal lobe, insula, and anterior cerebellum. A total of 321 subjects from ADNI-2, including 209 NC (18 progressive NC (pNC), 113 stable NC (sNC), and 78 remaining NC (rNC)) and 112 SCD (11 pSCD, 5 sSCD, and 96 rSCD), as well as 109 subjects from CLAS, including 17 sNC, 16 pNC, 52 sSCD and 24 pSCD participated in the test set, separately. We found that the PI score effectively sorted all subjects by their stages (stable vs progressive). Furthermore, the PI score demonstrated excellent discrimination between the two outcomes in the CLAS data(p<0.001), even after controlling for age, gender, education level, depression symptoms, anxiety symptoms, somatic diseases, and baseline MoCA score. Better performance for prediction progression to MCI in CLAS was obtained when the PI score was combined with clinical measures (AUC=0.812; 95 %CI: 0.725–0.900).
CONCLUSIONS: This study effectively predicted the progression to MCI among order individuals at normal cognition state by deep learning algorithm with MRI scans. Exploring the key brain alterations during the very early stages, specifically the transition from NC to MCI, based on deep learning methods holds significant potential for further research and contributes to a deeper understanding of disease mechanisms.
CITATION:
Ling Yue ; Yongsheng Pan ; Wei Li ; Junyan Mao ; Bo Hong ; Zhen Gu ; Mingxia Liu ; Dinggang Shen ; Shifu Xiao (2025): Predicting cognitive decline: Deep-learning reveals subtle brain changes in pre-MCI stage. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100079
INTERACTIONS OF PHYSICAL ACTIVITY AND LUNG FUNCTION ON COGNITIVE HEALTH IN OLDER ADULTS: JOINT ASSOCIATION AND MEDIATION ANALYSIS
Peng Hu, Dan Song, Tian Heng, Ling-Ling Yang, Chuan-Chuan Bai, Rui He, Tao Liu, Ya-Xi Luo, Xiu-Qing Yao
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Maintaining cognitive health in old adults has become a significant public health challenge, with lung function and physical activity (PA) as essential modifiable factors. However, the joint and mediation effects of these two factors with cognition remain unclear.
OBJECTIVES: This study assesses the joint association and mediation effects of lung function and PA with cognition.
DESIGN, SETTING, AND PARTICIPANTS: We utilized cross-sectional data from the 2011–2012 U.S. National Health and Nutrition Examination Survey, including adults aged 60–79 assessed for lung function, PA, and cognition.
MAIN OUTCOMES AND MEASURES: Lung function included forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF) and FEV1/FVC. PA was assessed using the Global Physical Activity Questionnaire, covering occupational PA (OPA), transportation-related PA (TPA), and leisure-time PA (LTPA). Cognition was evaluated using the Digit Symbol Substitution Test, Animal Fluency Test, Delayed Recall Test and Immediate Recall Test. Weighted multiple linear regression models were used to analyze the separate and joint associations of lung function and PA with cognition, while also exploring potential mediation effects between these factors.
RESULTS: A total of 927 participants, representing 35,525,782 U.S. residents, were included, with a weighted median age of 65 (IQR, 63 -71) years, and 53.6 % were female. The results showed a significant positive association between lung function and cognitive function, with FEV1, FVC, and PEF all positively correlated, while the FEV1/FVC showed no notable link. Further analysis revealed the best cognitive performance observed in participants with active LTPA and the highest quartile of lung function, indicating a joint association of LTPA and lung function with cognition. Mediation analysis indicated that lung function mediated 24.1 % (95 %CI: 6.3 % - 47.0 %, P = 0.03) of the relationship between LTPA and cognition, while cognition mediated 10.2 % (95 %CI: 0.5 % - 27.0 %, P = 0.04) of the relationship between LTPA and lung function.
CONCLUSION: Lung function and cognition may have a bidirectional relationship. The combination of active LTPA and better lung function was strongly associated with higher cognition, highlighting the need to strengthen exercise focused on lung function to maintain cognitive health in older adults.
CITATION:
Peng Hu ; Dan Song ; Tian Heng ; Ling-Ling Yang ; Chuan-Chuan Bai ; Rui He ; Tao Liu ; Ya-Xi Luo ; Xiu-Qing Yao (2025): Interactions of physical activity and lung function on cognitive health in older adults: Joint association and mediation analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100090
LMTK2 AND CRB1 ARE TWO NOVEL RISK GENES FOR ALZHEIMER\'S DISEASE IN HAN CHINESE
Xuewen Xiao, Hui Liu, Rui Yao, Yunni Li, Xinxin Liao, Yingzi Liu, Yafang Zhou, Junling Wang, Beisha Tang, Bin Jiao, Jinchen Li, Lu Shen, Shilin Luo
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with a substantial genetic background. However, its underlying genetic architecture remains to be elucidated.
METHODS: In this study, we performed whole-exome sequencing in 282 familial and/or early-onset AD patients and 1086 cognitively normal controls in the Han Chinse populations. According to minor allele frequency, variants were divided into common variants (MAF ≥ 0.01) and rare variants (MAF < 0.01). Common variant-based association analysis and gene-based association test aggregating rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal, respectively. We replicated the significant results by using the same AD samples and controls from whole genome sequencing (n = 1879). Furthermore, we determined the functions of the novel AD risk genes in vitro.
RESULTS: Common variants association analysis revealed that APOE rs429358 reached statistical whole-exome significance. Gene-level aggregation testing identified that rare damaging variants in LMTK2 and CRB1 conferred risk to AD. All variants are located in highly conserved amino acid regions and are predicted to be damaging. Furthermore, functional studies showed that LMTK2 rare damaging variants (R234P and S974G) enhanced tau phosphorylation levels, tau aggregates formation, and Aβ generation. Meanwhile, the CRB1 Y556X variant caused incomplete translation of CRB1 protein and increased the Aβ42 level and Aβ42/Aβ40 ratio.
CONCLUSION: Our findings indicated that LMTK2 and CRB1 are two novel AD risk genes in Han Chinese, which may provide promising targets for diagnosis and intervention.
CITATION:
Xuewen Xiao ; Hui Liu ; Rui Yao ; Yunni Li ; Xinxin Liao ; Yingzi Liu ; Yafang Zhou ; Junling Wang ; Beisha Tang ; Bin Jiao ; Jinchen Li ; Lu Shen ; Shilin Luo (2025): LMTK2 and CRB1 are two novel risk genes for Alzheimer's disease in Han Chinese. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100087
THE INTERACTION BETWEEN CIRCADIAN SYNDROME AND GENETIC SUSCEPTIBILITY IN THE RISK OF INCIDENT DEMENTIA: A LONGITUDINAL COHORT STUDY
Linling Yu, Wei Liu, Chenqi Liao, Na Shen, Anding Liu, Liming Cheng, Xiong Wang
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Despite growing interest in circadian disturbances as potential triggers for dementia, the specific impact of circadian syndrome (CircS) on dementia incidence remains poorly understood. Moreover, the role of genetic susceptibility modulating these effects remains to be explored.
METHODS: Dementia-free participants from the UK Biobank cohort were included in the analysis. To evaluate the association between CircS and the incidence of dementia, as well as the modifying influence of genetic susceptibility on this relationship, Cox proportional hazards models were utilized.
RESULTS: During a median follow-up period of 14.55 years, 3,965 incident dementia cases were documented. CircS was found to significantly increased the risk of incident dementia, with a hazard ratio (HR) of 1.401 (95 % confidence interval [CI]: 1.296, 1.516). Compared to a CircS score of ≤3, mild CircS (HR: 1.259, 95 % CI: 1.146–1.383), moderate CircS (HR: 1.667, 95 % CI: 1.461–1.903), and severe CircS (HR: 2.028, 95 % CI: 1.397–2.944) were all significantly associated with an elevated risk of dementia. There were significant multiplicative interactions between CircS and genetic susceptibility (Pinteraction<0.001). Participants with both a high polygenic risk score (PRS) and CircS had the highest risk of incident dementia (HR: 2.551, 95 % CI: 2.169, 3.001), compared to those with a low PRS and no CircS.
CONCLUSIONS: CircS was associated with an increased risk of dementia, which might be aggravated by genetic susceptibility.
CITATION:
Linling Yu ; Wei Liu ; Chenqi Liao ; Na Shen ; Anding Liu ; Liming Cheng ; Xiong Wang (2025): The interaction between circadian syndrome and genetic susceptibility in the risk of incident dementia: A longitudinal cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100089
DIAGNOSTIC AND DISCRIMINATIVE ACCURACY OF PLASMA PHOSPHORYLATED TAU 217 FOR SYMPTOMATIC ALZHEIMERʼS DISEASE IN A CHINESE COHORT
Li-Min Li, Ping Che, Dequan Liu, Yu Wang, Jia Li, Dian He, Tao Liu, Nan Zhang
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Plasma phosphorylated tau at threonine 217 (p-tau217) measured with an ultrasensitive immunoassay method has been demonstrated to be an optimal biomarker for Alzheimer's disease (AD).
OBJECTIVES: The aim of this study was to establish the reference interval for plasma p-tau217 in Chinese individuals and evaluate its diagnostic value in symptomatic AD.
DESIGN, SETTING, PARTICIPANTS: We recruited 150 cognitively unimpaired (CU) individuals, 60 patients with AD dementia, 30 patients with mild cognitive impairment (MCI) due to AD, 40 patients with frontotemporal lobar degeneration (FTLD), and 70 patients with subcortical ischaemic vascular dementia (SIVD).
MEASUREMENTS: The concentrations of plasma p-tau217, total tau, amyloid-beta (Aβ)42 and Aβ40 were measured with a single-molecule array.
RESULTS: Plasma p-tau217 outperformed other biomarkers in discriminating AD patients from CU controls, FTLD patients, and SIVD patients (AUC = 0.983, 0.936, 0.892) and discriminating MCI patients from CU controls (AUC = 0.943). The plasma p-tau217 level was negatively correlated with memory in patients with symptomatic AD.
CONCLUSION: The diagnostic accuracy of plasma p-tau217 was exceptional for AD, even at early stages, in the Chinese population.
CITATION:
Li-Min Li ; Ping Che ; Dequan Liu ; Yu Wang ; Jia Li ; Dian He ; Tao Liu ; Nan Zhang (2025): Diagnostic and discriminative accuracy of plasma phosphorylated tau 217 for symptomatic Alzheimerʼs disease in a Chinese cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100092
MULTISENSORY STIMULATION REDUCES NEUROPSYCHIATRIC SYMPTOMS AND ENHANCES COGNITIVE FUNCTION IN OLDER ADULTS WITH DEMENTIA: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Tiara Octary, Melati Fajarini, Hidayat Arifin, Ruey Chen, Chien-Mei Sung, Li-Fang Chang, Chia-Hui Wang, Kondwani Joseph Banda, Kuei-Ru Chou
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryOBJECTIVE: Multisensory stimulation defined as engaging multiple senses (visual, olfactory, auditory, gustatory, and tactile), has been demonstrated to improve older adults’ general health. However, its effectiveness in mitigating neuropsychiatric symptoms (NPSs) and cognitive deficits in older adults with dementia remains unclear. This meta-analysis evaluated the efficacy of multisensory stimulation in ameliorating NPSs and improving overall cognitive function in older adults with dementia.
METHODS: We searched eight databases to September 2024 without restriction. Older adults with all stages of dementia aged 65 years and above were included. To estimate the pooled effect size, Hedge's g (g) values were calculated using a random-effects model. Heterogeneity was assessed using the Q, I², and τ² statistics. Subgroup and meta-regression analyses were performed to identify moderators. Publication bias was assessed using Begg and Mazumdar's rank correlation and Egger's linear regression tests.
RESULTS: This review included 16 studies (974 patients). Multisensory stimulation significantly reduced agitation (g= −0.96; 95 %CI= −1.44, −0.48), apathy (g= −1.27; 95 %CI= −2.08, −0.46), and depression (g= −0.28; 95 %CI= −0.48, −0.07). Moreover, the intervention significantly improved overall cognitive function (g= 0.30; 95 %CI= 0.09, 0.52). However, multisensory stimulation had no significant effect on anxiety (g= −0.81; 95 %CI= −1.79, 0.17). Significant heterogeneity was observed in agitation, apathy, and anxiety. Moreover, meta-regression analyses by educational level (junior high school and above) revealed significant moderators in agitation.
CONCLUSIONS: Multisensory stimulation shows promise as a non-pharmacological intervention for older adults with dementia. It may effectively mitigate NPSs and improve cognitive function into clinical practice as an alternative therapeutic.
CITATION:
Tiara Octary ; Melati Fajarini ; Hidayat Arifin ; Ruey Chen ; Chien-Mei Sung ; Li-Fang Chang ; Chia-Hui Wang ; Kondwani Joseph Banda ; Kuei-Ru Chou (2025): Multisensory stimulation reduces neuropsychiatric symptoms and enhances cognitive function in older adults with dementia: A meta-analysis of randomized controlled trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100091
INTEGRATIVE SINGLE-CELL RNA SEQUENCING AND MENDELIAN RANDOMIZATION ANALYSIS REVEAL THE POTENTIAL ROLE OF SYNAPTIC VESICLE CYCLING-RELATED GENES IN ALZHEIMER\'S DISEASE
Junfeng Zeng, Ruihua Zhang, Huihua Xu, Chengwu Zhang, Li Lu
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: Alzheimer's disease (AD) involves alterations in synaptic vesicle cycling (SVC), which significantly affect neuronal communication and function. Therefore, a thorough investigation into the potential roles of SVC-related genes (SVCRGs) in AD can enhance the identification of critical biomarkers that may influence disease progression and treatment responses.
METHODS: The datasets used in this study were sourced exclusively from public databases. By integrating differential expression analysis with Mendelian randomization (MR), we identified SVCRGs as biomarkers for AD. Functional characterization of these biomarkers was performed, followed by integration into a nomogram. Further investigation of immune infiltration in AD patients and healthy individuals was carried out. Ultimately, the potential cellular mechanisms of AD were explored through single-cell RNA sequencing (scRNA-seq) analysis.
RESULTS: ATP6V1D, ATP6V1G2, CLTB, and NSF were identified as biomarkers, exhibiting a positive correlation with each other and a downregulated expression in AD. These markers were pinpointed as protective factors for AD [odds ratio (OR) < 1, P < 0.05], with potential to reduce the risk of the disease. Integrated into a nomogram, they demonstrated satisfactory diagnostic performance and clinical utility, surpassing the use of single gene. They were collectively enriched in pathways related to "interferon gamma response", "inflammatory response", and "TNFα signaling via NFκB". Additionally, an increase in infiltration of 17 immune cell types in AD was noted, particularly cells associated with neuroinflammation such as activated CD8 T cells and various dendritic cells (DCs), suggesting an inflammatory milieu in AD while also displaying a negative correlation with the biomarkers. The cell types were further annotated, revealing specific expressions of biomarkers and uncovering the heterogeneity of excitatory neurons. A significant reduction in the overall number of excitatory neurons under AD conditions was observed, alongside consistent expression of biomarkers during the developmental stages of excitatory neurons.
CONCLUSION: By using MR, we firstly identified four SVCRGs as protective factors for AD, functioning through pathways associated with mitochondrial dysfunction, chronic inflammation, immune dysregulation, and neuronal damage. These genes had the potential to modulate immune cell infiltration activated in AD patients and exhibited cell-type-specific expression profiles within AD-related cellular contexts. Their findings provide novel insights and valuable references for future research on AD pathogenesis and therapeutic strategies.
CITATION:
Junfeng Zeng ; Ruihua Zhang ; Huihua Xu ; Chengwu Zhang ; Li Lu (2025): Integrative single-cell RNA sequencing and mendelian randomization analysis reveal the potential role of synaptic vesicle cycling-related genes in Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100097
CURRENT STATUS AND FUTURE DIRECTIONS FOR THE DIAGNOSIS AND MANAGEMENT OF MILD COGNITIVE IMPAIRMENT IN SOUTHEAST ASIA: A SEACURE CONSENSUS PAPER
Gursimar Bhalla, Pricilia Tanoto, Ashwati Vipin, Xiao Yuan James Chen, Yi Jin Leow, Christopher Chen, Philip Lin Kiat Yap, Reshma A Merchant, Saima Hilal, Anam Paulus Ong, Encarnita Raya Ampil, Mohamad Imran Idris, Irene Looi, Jacqueline Dominguez, Suraya Yusoff, Maw Pin Tan, Cong Thang Tran, Mai Trang Tong, Vorapun Senanarong, Yuda Turana, Nagaendran Kandiah
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryGlobal aging populations are facing increased prevalence of mild cognitive impairment (MCI) – the preclinical stage of dementia characterized by single/multi-domain neurocognitive decline that does not impair an individual's normal daily functioning. Asian populations are at increased risk of developing MCI and dementia, and many cases go undetected in Southeast Asia (SEA), resulting in increased burden on patients, caregivers and national healthcare systems. There is an urgent need for efficient and scalable diagnostic and management strategies across SEA. Our findings illustrate that current strategies are limited by insufficient resources and a lack of awareness, particularly in developing SEA nations. Strategies for improving the MCI landscape in SEA include increasing widespread community awareness and cognitive health screenings for individuals with a history of vascular risk factors, validation of traditional cognitive screening tests in the respective countries, greater access to blood-biomarker testing, and the development and validation of novel digitized diagnostics.
CITATION:
Gursimar Bhalla ; Pricilia Tanoto ; Ashwati Vipin ; Xiao Yuan James Chen ; Yi Jin Leow ; Christopher Chen ; Philip Lin Kiat Yap ; Reshma A Merchant ; Saima Hilal ; Anam Paulus Ong ; Encarnita Raya Ampil ; Mohamad Imran Idris ; Irene Looi ; Jacqueline Dominguez ; Suraya Yusoff ; Maw Pin Tan ; Cong Thang Tran ; Mai Trang Tong ; Vorapun Senanarong ; Yuda Turana ; Nagaendran Kandiah (2025): Current status and future directions for the diagnosis and management of mild cognitive impairment in Southeast Asia: A SEACURE consensus paper. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100110
THE DISEASE BURDEN, RISK FACTORS AND FUTURE PREDICTIONS OF ALZHEIMER\'S DISEASE AND OTHER TYPES OF DEMENTIA IN ASIA FROM 1990 TO 2021
Jinxuan Guo, Pin Wang, Jin Gong, Wenxian Sun, Xiaodong Han, Chang Xu, Aidi Shan, Xin Wang, Heya Luan, Shaoqi Li, Ruina Li, Boye Wen, Runqi Chen, Sirong Lv, Cuibai Wei
J Prev Alz Dis 2025;5(12)
Show summaryHide summaryBACKGROUND: There is a lack of analysis and prediction of the disease burden of Alzheimer's disease and other dementias (ADOD) in Asia.
OBJECTIVES: This study aims to explore the impact of ADOD on the Asian region during the period from 1990 to 2021.
DESIGN: Data on ADOD in Asia from 1990 to 2021 were collected from the Global Burden of Disease (GBD) Study 2021. We analyzed the number and age-standardized rates (ASRs) of incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) of ADOD from 1990 to 2021. Joinpoint regression analysis was performed, and the average annual percent changes (AAPCs) were calculated to evaluate the trends during this period. Subsequently, an auto - regressive integrated moving average (ARIMA) prediction model analysis was conducted to assess the trends in the next 30 years, aiming to report the epidemiology and disease burden of ADOD in Asia.
RESULTS: According to the analysis of the GBD database in 2021, the deaths, DALYs, incidence, and prevalence of ADOD increased by 297.34 %, 249.54 %, 244.73 %, and 250.44 % in Asia from 1990 to 2021. The ASRs of incidence, prevalence, death, and DALYs in both males and females, which consistently increased over the study period, showed that the ASRs of all females were consistently higher than those of males in Asia from 1990 to 2021. During the period from 1990 to 2021, Qatar and the United Arab Emirates witnessed the greatest changes in the number of DALYs, incidence, and prevalence. Afghanistan and China had the highest age-standardized mortality rate (ASMR) in 2021. It is worth noting that high fasting blood glucose is the top risk factor for the onset of ADOD. Females are more susceptible to the risk factor of high body-mass index (BMI), while males are more likely to be affected by smoking. According to the analysis of the ARIMA prediction model, the disease burden of ADOD in Asia will continue to show an upward trend in the next 30 years.
CONCLUSIONS: We should pay attention to the issue of population aging, attach importance to the intervention measures targeting the risk factors of ADOD, and formulate action plans to address the rising incidence of ADOD.
CITATION:
Jinxuan Guo ; Pin Wang ; Jin Gong ; Wenxian Sun ; Xiaodong Han ; Chang Xu ; Aidi Shan ; Xin Wang ; Heya Luan ; Shaoqi Li ; Ruina Li ; Boye Wen ; Runqi Chen ; Sirong Lv ; Cuibai Wei (2025): The disease burden, risk factors and future predictions of Alzheimer's disease and other types of dementia in Asia from 1990 to 2021. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100122
LETTER TO THE EDITOR: ENHANCING STATIN RESEARCH FOR ALZHEIMER\'S PREVENTION: SUGGESTIONS FOR FUTURE STUDIES AND POLICY IMPLICATIONS
Yumei Zhong, Shanshan Liu, Xiaofeng Lv
J Prev Alz Dis 2025;5(12)
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CITATION:
Yumei Zhong ; Shanshan Liu ; Xiaofeng Lv (2025): Letter to the Editor: Enhancing statin research for Alzheimer's prevention: Suggestions for future studies and policy implications. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100118
REPLY TO THE LETTER TO THE EDITOR: ENHANCING STATIN RESEARCH FOR ALZHEIMER\'S PREVENTION: SUGGESTIONS FOR FUTURE STUDIES AND POLICY IMPLICATIONS
Zirong Ye, Jiahe Deng, Xiuxia Wu, Jingwen Cai, Sicheng Li, Xiaochun Chen, Jiawei Xin
J Prev Alz Dis 2025;5(12)
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CITATION:
Zirong Ye ; Jiahe Deng ; Xiuxia Wu ; Jingwen Cai ; Sicheng Li ; Xiaochun Chen ; Jiawei Xin (2025): Reply to the letter to the Editor: Enhancing Statin Research for Alzheimer's Prevention: Suggestions for Future Studies and Policy Implications. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100119
LETTER TO THE EDITOR: CONCERNS ABOUT ANAVEX\'S CLINICAL TRIAL OF BLARCAMESINE
Jesse Brodkin
J Prev Alz Dis 2025;5(12)
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CITATION:
Jesse Brodkin (2025): Letter to the Editor: Concerns about Anavex's clinical trial of Blarcamesine. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100137
LETTER TO THE EDITOR: REBUTTAL LETTER ON BEHALF OF ALL AUTHORS IN RESPONSE TO THE LETTER TO THE EDITOR
Marwan Noel Sabbagh
J Prev Alz Dis 2025;5(12)
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CITATION:
Marwan Noel Sabbagh (2025): Letter to the Editor: Rebuttal letter on behalf of all authors in response to the Letter to the Editor. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100136
CORRIGENDUM TO “ENHANCING DEMENTIA PREDICTION: A 19-YEAR VALIDATION OF THE CAIDE RISK SCORE WITH INSULIN RESISTANCE AND APOE ε4 INTEGRATION IN A POPULATION-BASED COHORT” [THE JOURNAL OF PREVENTION OF ALZHEIMER\'S DISEASE (2024) 100034]
Elina Pietilä, Eliisa Löyttyniemi, Seppo Koskinen, Jenni Lehtisalo, Matti Viitanen, Juha O. Rinne, Antti Jula, Laura L. Ekblad
J Prev Alz Dis 2025;5(12)
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CITATION:
Elina Pietilä ; Eliisa Löyttyniemi ; Seppo Koskinen ; Jenni Lehtisalo ; Matti Viitanen ; Juha O. Rinne ; Antti Jula ; Laura L. Ekblad (2025): Corrigendum to “Enhancing Dementia Prediction: A 19-Year Validation of the CAIDE Risk Score with Insulin Resistance and APOE ε4 Integration in a Population-Based Cohort” [The Journal of Prevention of Alzheimer's Disease (2024) 100034]. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100158