Kyungtae Kim, Min Soo Byun, Dahyun Yi, Joon Hyung Jung, Bo Kyung Sohn, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Yun-Sang Lee, Yu Kyeong Kim, Kwangsik Nho, Dong Young Lee
{"title":"Serum BDNF and progression to MCI in cognitively normal older adults: A prospective cohort study.","authors":"Kyungtae Kim, Min Soo Byun, Dahyun Yi, Joon Hyung Jung, Bo Kyung Sohn, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Yun-Sang Lee, Yu Kyeong Kim, Kwangsik Nho, Dong Young Lee","doi":"10.1016/j.tjpad.2025.100210","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100210","url":null,"abstract":"<p><strong>Background: </strong>Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the mammalian brain. Preclinical studies suggest that BDNF influences the pathophysiology of Alzheimer's disease. In humans, higher blood BDNF levels have been associated with a lower risk of dementia. However, the relationship between serum BDNF levels and the progression to mild cognitive impairment (MCI) in cognitively normal (CN) individuals remains uncertain.</p><p><strong>Objectives: </strong>To examine whether higher serum BDNF levels in CN older adults are associated with a reduced incidence of MCI over a 4-year follow-up period and to identify potential moderators of this relationship.</p><p><strong>Design: </strong>Longitudinal analyses were conducted using follow-up data from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study. Data were collected from January 1, 2014, to May 31, 2021, and analyzed from May 1, 2023, to September 30, 2023.</p><p><strong>Setting: </strong>Community and memory clinic setting.</p><p><strong>Participants: </strong>A total of 274 CN older adults aged 55-90 years were included at baseline.</p><p><strong>Measurement: </strong>Progression to MCI over the 4-year follow-up period.</p><p><strong>Results: </strong>Among the 274 participants, 26 developed MCI during follow-up. The high BDNF group had a significantly lower incidence of MCI compared to the low BDNF group (hazard ratio [HR], 0.27; 95 % confidence interval [CI], 0.11-0.69; P = 0.006). This association persisted even after adjusting for BDNF Val66Met polymorphism, amyloid PET positivity, vascular risk factors, cholesterol levels, triglycerides, homocysteine, BMI, smoking, alcohol, TBI history, CES-D, and MMSE scores (HR, 0.14; 95 % CI, 0.05-0.40; P < 0.001). Subgroup analyses further revealed that the association was significant only in women (HR, 0.12; 95 % CI, 0.03-0.48; P = 0.002), individuals aged <75 years (HR, 0.16; 95 % CI, 0.03-0.77; P = 0.022), those with less than a college degree (HR, 0.23; 95 % CI, 0.07-0.74; P = 0.013), and amyloid PET-negative (HR, 0.29; 95 % CI, 0.11-0.72; P = 0.014) individuals.</p><p><strong>Conclusions: </strong>These findings suggest a protective role of BDNF against clinical progression to MCI in cognitively healthy older individuals. This effect appears to be more prominent in women, as well as in relatively younger, less educated, and amyloid PET-negative individuals.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100210"},"PeriodicalIF":4.3,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jackson Burton, Holly M Brothers, R Matthew Hutchison, Jennifer Murphy, Tao Sun, Gersham Dent, Gioacchino Curiale, Ken Kowalski
{"title":"Lower baseline amyloid beta burden is associated with greater percent of amyloid beta positron emission tomography reduction and better clinical outcomes in the aducanumab Phase 3 trials ENGAGE and EMERGE in early Alzheimer's disease.","authors":"Jackson Burton, Holly M Brothers, R Matthew Hutchison, Jennifer Murphy, Tao Sun, Gersham Dent, Gioacchino Curiale, Ken Kowalski","doi":"10.1016/j.tjpad.2025.100202","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100202","url":null,"abstract":"<p><strong>Background: </strong>Aducanumab is a human immunoglobulin G1 anti-amyloid beta antibody for early-stage Alzheimer's disease. After the discontinuation of the aducanumab clinical program and market withdrawal, the Phase 3 data were further assessed to characterize the relationship between baseline amyloid beta load, degree of amyloid beta removal, and subsequent clinical outcomes to provide context for future research.</p><p><strong>Objectives: </strong>This analysis leveraged modelling techniques to impute missing amyloid beta positron emission tomography values and better understand the relationship between baseline amyloid beta positron emission tomography status, amyloid beta positron emission tomography reduction, and clinical outcomes in the aducanumab Phase 3 ENGAGE and EMERGE (NCT02477800/NCT02484547) studies.</p><p><strong>Design: </strong>Exploratory data analysis.</p><p><strong>Setting: </strong>A previously developed model which characterized the relationship between aducanumab exposure and amyloid beta positron emission tomography standard uptake value ratio was updated to impute centiloid values for participants not enrolled in the amyloid beta positron emission tomography substudy. Additional clinically-relevant variables were also summarized.</p><p><strong>Participants: </strong>1876 participants with baseline amyloid beta positron emission tomography and clinical endpoints in a pooled ENGAGE/EMERGE dataset at week 78.</p><p><strong>Intervention: </strong>Aducanumab MEASUREMENTS: Amyloid burden measured by centiloids and clinical endpoints.</p><p><strong>Results: </strong>In older participants whose baseline amyloid beta burden is lower than the average trial population, exposure to aducanumab provides greater clinical benefit across cognitive and functional endpoints.</p><p><strong>Conclusions: </strong>The relationship between baseline amyloid beta load and treatment benefit in a large population after exposure to an amyloid beta-directed antibody provides insight into which subpopulations are likely to benefit from this class of treatment.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100202"},"PeriodicalIF":4.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comment on \"Hearing loss, diet, and cognitive decline: interconnections for dementia prevention\".","authors":"Cuiqing Zhao, Jian Gong, Jia Huang","doi":"10.1016/j.tjpad.2025.100189","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100189","url":null,"abstract":"","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100189"},"PeriodicalIF":4.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Brain health PRO/santé cerveau PRO: The development of a web-based program for dementia literacy and risk factor reduction.","authors":"Alex Bahar-Fuchs","doi":"10.1016/j.tjpad.2025.100206","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100206","url":null,"abstract":"","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100206"},"PeriodicalIF":4.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
{"title":"Drug delivery strategies to cross the blood-brain barrier in Alzheimer's disease: a comprehensive review on three promising strategies.","authors":"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","doi":"10.1016/j.tjpad.2025.100204","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100204","url":null,"abstract":"<p><p>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. <sup>89</sup>Zr-Immuno-PET provides a unique opportunity to noninvasively monitor and quantitatively assess novel brain delivery methods.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100204"},"PeriodicalIF":4.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Herpes zoster and dementia : more evidences for a causal link.","authors":"Jean-François Dartigues, Morgane Linard","doi":"10.1016/j.tjpad.2025.100201","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100201","url":null,"abstract":"","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100201"},"PeriodicalIF":4.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jee Wook Kim, Musung Keum, Min Soo Byun, Dahyun Yi, So Yeon Jeon, Joon Hyung Jung, Nayeong Kong, Yoon Young Chang, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Koung Mi Kang, Chul-Ho Sohn, Yun-Sang Lee, Yu Kyeong Kim, Dong Young Lee
{"title":"Lifetime walking and Alzheimer's pathology: A longitudinal study in older adults.","authors":"Jee Wook Kim, Musung Keum, Min Soo Byun, Dahyun Yi, So Yeon Jeon, Joon Hyung Jung, Nayeong Kong, Yoon Young Chang, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Koung Mi Kang, Chul-Ho Sohn, Yun-Sang Lee, Yu Kyeong Kim, Dong Young Lee","doi":"10.1016/j.tjpad.2025.100203","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100203","url":null,"abstract":"<p><strong>Importance: </strong>While many studies have shown that greater amounts or longer durations of walking are associated with a lower risk of Alzheimer's disease (AD) or cognitive decline in older adults, the neuropathological basis for this is not yet fully understood.</p><p><strong>Objective: </strong>To examine the relationship between walking intensity and duration and longitudinal changes in Alzheimer's disease (AD)-related brain pathologies, including Aβ and tau accumulation, neurodegeneration, and white matter hyperintensity (WMH).</p><p><strong>Design: </strong>Data were drawn from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, a longitudinal cohort study (initiated in 2014).</p><p><strong>Setting: </strong>Community and memory clinic setting.</p><p><strong>Participants: </strong>One hundred fifty-one older adults.</p><p><strong>Main outcome and measures: </strong>Participants underwent baseline and 4-year follow-up neuroimaging assessments. Lifetime walking, as measured using the Lifetime Total Physical Activity Questionnaire, was categorized by intensity (high vs. low) and duration (short ≤360 min/week vs. long >360 min/week), forming four combined walking groups. Aβ and tau deposition, neurodegeneration, and WMH volume were assessed via PET/MRI.</p><p><strong>Results: </strong>Long-duration or high-intensity walking was associated with significantly reduced Aβ accumulation over 4 years. The high-combined walking group showed similar benefits, while medium-combined groups did not. The effect was significant only in the early life-initiated walking subgroup. No associations were found with tau, neurodegeneration, or WMH volume.</p><p><strong>Conclusions: </strong>Long-duration, high-intensity walking may reduce brain Aβ accumulation, potentially lowering AD risk, particularly when initiated before late life.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100203"},"PeriodicalIF":4.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Causal relationship and mediating role between depression and cognitive performance.","authors":"Xinyu Hao, Fuyang Cao, Ziyao Xu, Shaohua You, Tianyue Mi, Lei Wang, Yongxin Guo, Zhuoning Zhang, Jiangbei Cao, Jingsheng Lou, Yanhong Liu, Xianyang Chen, Zhikang Zhou, Weidong Mi, Li Tong","doi":"10.1016/j.tjpad.2025.100196","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100196","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have increasingly emphasized the robust correlation between depression and cognitive function. However, it remains unclear whether this relationship is causal or merely coincidental. To address this uncertainty, we conducted two-sample bidirectional Mendelian randomization (MR) analyses to investigate the connection between depression and cognitive performance.</p><p><strong>Methods: </strong>We sourced genome-wide association study (GWAS) data for depression (N<sub>SNPs</sub>=21,306,230) from the FinnGen (R10) and for cognitive performance (N<sub>SNPs</sub>=10,049,954) from the IEU GWAS database. Causal effects employed methodologies such as Inverse variance weighted (IVW), weighted median, MR Egger, simple mode and weighted mode. Two-step analysis determined the contribution of the mediator variable to the outcomes. To determine stability and reliability, sensitivity analyses were performed that included an assessment of heterogeneity, horizontal pleiotropy, and the leave-one-out techniques.</p><p><strong>Results: </strong>This MR analysis identified 8 independent significant SNPs associated with depression and 81 SNPs linked to cognitive performance. Our findings revealed that depression increases the risk of developing deteriorating cognitive performance (IVW β, -0.11; 95 % confidence interval (CI), -0.18 - -0.05; P<sub>IVW</sub> value= 5.97E-04). Conversely, cognitive performance decline could also predispose individuals to depression [odds ratio (OR)<sub>IVW,</sub> 0.85; 95 % CI, 0.76 - 0.95; P<sub>IVW</sub> value=0.004]. Multivariate MR analysis confirmed the robustness of this bidirectional association. A two-step MR mediation analysis indicated that the pathway from depression to cognitive performance is mediated by pain, with a mediation effect size of -0.022 and a mediation ratio of 28.95 %. The pathway from cognitive performance to depression is mediated by frailty, with a mediation effect value of -0.028, representing 22.40 % of the mediation proportion.</p><p><strong>Conclusion: </strong>A two-way causal relationship between depression and cognitive performance, with pain and frailty being mediating factors, respectively. Future research should prioritize mechanistic studies, targeted interventions, and personalized approaches to disentangle and mitigate the bidirectional effects of depression and cognitive performance.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100196"},"PeriodicalIF":4.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Avi Cohen, Stephen Z Levine, Gabriel Vainstein, Michal Schnaider Beeri, Galit Weinstein
{"title":"New-generation antidiabetic medications and dementia risk in older adults with type 2 diabetes: A retrospective cohort study.","authors":"Avi Cohen, Stephen Z Levine, Gabriel Vainstein, Michal Schnaider Beeri, Galit Weinstein","doi":"10.1016/j.tjpad.2025.100199","DOIUrl":"https://doi.org/10.1016/j.tjpad.2025.100199","url":null,"abstract":"<p><strong>Background: </strong>New-generation antidiabetic medications may have therapeutic potential for dementia, beyond their glycemic effects. However, information from observational studies exploring the association between new-generation antidiabetic use and dementia risk is limited.</p><p><strong>Objectives: </strong>To examine the association between new-generation antidiabetic medication use and dementia risk.</p><p><strong>Design: </strong>Retrospective cohort study using electronic health records of a large non-profit health maintenance organization.</p><p><strong>Participants: </strong>84,798 dementia-free individuals aged ≥65y with type 2 diabetes.</p><p><strong>Measurements: </strong>Antidiabetic medication exposure was based on purchased prescriptions and was used as a time-varying variable. Exposure periods were defined as periods in which either dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), or glucagon-like peptide-1 analogs (GLP-1a) or their combinations were used, otherwise unexposed. Dementia classification was based on the International Classification of Diseases, Ninth Revision codes or antidementia medication prescriptions. Cox regression models were fitted to quantify the association between antidiabetic medication use and incident dementia. Models were adjusted for 13 potential sources of confounding using inverse-probability weighting.</p><p><strong>Results: </strong>Among 84,798 individuals with a mean diabetes onset age of 66.4 ± 7.5 years, the median follow-up for dementia risk was 8.7 years (Q1-Q3: 5.4-12.8). Dementia was diagnosed in 11,642 (13.7%) individuals. New-generation medication use was associated with reduced dementia risk (HR = 0.69; 95% CI, 0.66-0.73) and by drug classes (DPP-4i, HR 0.67 [95% CI 0.63-0.71]; SGLT-2i, 0.63 [95% CI 0.56-0.70], GLP-1a, 0.61 [95% CI 0.54-0.69].</p><p><strong>Conclusions: </strong>The results of this large-scale study suggest that new-generation antidiabetic medication use may be associated with lower dementia risk in older adults with T2D.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100199"},"PeriodicalIF":4.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}