Journal of Alzheimer's Disease最新文献

{"title":"The role of microglia glucose metabolism reprogramming in Alzheimer's disease treatment.","authors":"Qingyu Cao, Mengmeng Shen, Yan Liu, Caicai Li, Lu Liu, Jidong Zhou, Rujing Yue, Dejun Niu, Yayun Ren, Lihong Pan, Jingchun Yao, Guimin Zhang","doi":"10.1177/13872877261478594","DOIUrl":"https://doi.org/10.1177/13872877261478594","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, and there remains a lack of effective treatments capable of reversing or significantly slowing disease progression. Accumulating evidence indicates that the immune function of microglia, the resident immune cells of the central nervous system, is a critical factor in regulating AD pathogenesis. Emerging research in immunometabolism further reveals that glucose metabolic reprogramming serves as a central driver of microglial phenotypic and functional differentiation. This review systematically outlines the fundamental characteristics of microglial glucose metabolism and focuses on how the dynamic metabolic reprogramming it undergoes during AD progression regulates microglial immune behavior and inflammatory responses. Building on this, we further summarize key regulatory targets within the \"metabolism-immune axis\" and corresponding pharmacological intervention strategies. Finally, this article discusses current challenges and future research directions in the field of microglial immunometabolism. This review aims to provide a theoretical foundation for AD intervention strategies targeting the \"metabolism-immune axis\" and to offer insights for the development of novel disease-modifying therapeutics.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261478594"},"PeriodicalIF":3.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148793434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of psychosocial factors on neurocognitive functioning in family caregivers of persons with Alzheimer's disease and related dementias.","authors":"Lauren Elliott, Emily Post, Anna McClendon, Jonathan Singer","doi":"10.1177/13872877261476965","DOIUrl":"https://doi.org/10.1177/13872877261476965","url":null,"abstract":"<p><p>BackgroundLimited research has examined neurocognitive decline in family caregivers of persons with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), despite most caregivers being over 65 and more susceptible to age-related declines due to increased stressors. The lack of insight into how psychosocial factors interact with caregivers' neurocognitive functioning limits our ability to identify targets for reducing neurocognitive risk.ObjectiveInvestigate the effects of psychosocial factors on neurocognitive functioning of AD/ADRD caregivers.MethodsThe caregiver sample (<i>n</i> = 42) consisted predominantly of older adults (<i>M</i>_age = 69.40, <i>SD</i>_age = 11.58) who were caring for a spouse (64.3%). On average, caregivers provided 99 h of care per week for several years (<i>M</i> = 3.42, <i>SD</i> = 2.39). Multiple linear regressions were conducted to examine the effects of psychological (i.e., depression, anxiety, pre-death grief, perceived stress) and social (i.e., social support, social network) factors on caregivers' neurocognitive functioning (i.e., visuospatial memory, verbal memory, processing speed, intelligence, executive functioning).ResultsSocial support significantly predicted visuospatial memory and processing speed. As social support increased, delayed visuospatial memory and processing speed improved when controlling for social network size.ConclusionsCaregivers may face additional stressors and have limited time or opportunities for social engagement. Social support may be especially important for spousal caregivers losing a primary support source (i.e., spouse). Findings suggest social support is a potential intervention target for reducing caregivers' risk of neurocognitive decline.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261476965"},"PeriodicalIF":3.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148793445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Explainable 3D deep learning from full-head MRI suggests scalp and skull involvement in Alzheimer's disease.","authors":"Mona Ebadi Jalal, Ramin Hamidi, Bryan Harris, Adel Elmaghraby, Robert P Friedland","doi":"10.1177/13872877261478312","DOIUrl":"https://doi.org/10.1177/13872877261478312","url":null,"abstract":"<p><p>BackgroundEmerging evidence suggests that extracranial tissues and immune-glymphatic interactions may contribute to neurodegenerative processes in Alzheimer's disease (AD). In this context, neuroimaging studies typically focus on intracranial brain structures, often excluding extracranial structures and adjacent meningeal regions through preprocessing steps.ObjectiveTo investigate whether full-head MRI contains potentially relevant information beyond the brain and whether explainable deep learning can identify spatial patterns associated with AD, mild cognitive impairment (MCI), and cognitively normal (CN) subjects.MethodsAn explainable full-head 3D deep learning framework based on DenseNet-121 with transfer learning from MedicalNet was proposed and applied to T1 MP-RAGE MRI data from the ADNI dataset. The model was trained on full-head MRI volumes without skull stripping using subject-level splits and evaluated across clinically relevant classification scenarios. Grad-CAM was used to localize regions contributing to model predictions.ResultsIn the three-class task (AD, CN, MCI), the model achieved 75.00% accuracy and 86.09% ROC-AUC. Performance was highest for distinguishing AD from CN (91.07% accuracy, 95.16% ROC-AUC) and remained strong for the combined (AD + MCI) versus CN (85.58% accuracy, 96.17% ROC-AUC). Explainability analysis revealed consistent saliency patterns not only within intracranial regions but also in peripheral regions, which may correspond to extracranial structures, such as scalp and skull.ConclusionsFull-head MRI may contain complementary, potentially diagnostically relevant information beyond the brain. Peripheral saliency patterns identified by our framework suggest a broader anatomical context for signals associated with AD. These findings are hypothesis-generating and require further validation across independent datasets and clinical studies, motivating targeted investigation.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261478312"},"PeriodicalIF":3.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148793476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptation and feasibility of the International Registry for Alzheimer's Disease and Other Dementias real-world datasets in old-age mental healthcare practice in China.","authors":"Haifeng Zhang, Jinghan Lai, Tao Wang, Tao Li, Sha Liu, Da-Liang Sun, Wei Chen, Weihong Kuang, Xia Li, Ming Zhang, Zhengluan Liao, Xiaojun Xiang, Maimaitirexiati Tuerxun, Xiangrong Zhang, Nan Zhang, Shifu Xiao, Frank Jessen, Enyan Yu, Xin Yu, Huali Wang","doi":"10.1177/13872877261478137","DOIUrl":"https://doi.org/10.1177/13872877261478137","url":null,"abstract":"<p><p>BackgroundAnti-amyloid disease-modifying therapies (DMTs) for early Alzheimer's disease (AD) are entering routine care, increasing the need for harmonized, registry-ready real-world data. The International Registry for Alzheimer's Disease and Other Dementias (InRAD) proposed a minimum dataset (MDS) and extended dataset (EDS), but their applicability to psychiatry-led old age mental healthcare practices in China is uncertain.ObjectiveTo adapt the InRAD dataset for real-world AD DMT practice across multiple psychiatry institutions in China and assess the feasibility of routine data capture for the proposed MDS/EDS.MethodsWe conducted a modified Delphi consensus study and a multicenter feasibility survey. Forty-nine experts classified domains/items into the MDS or EDS using predefined agreement thresholds. Thirty-five DMT-initiating mental healthcare teams reported the routine availability of the proposed data elements.ResultsHighly consistent with InRAD, ten domains were included in the China-adapted MDS/EDS, covering patient profiles and lifestyle, diagnostic work-up and biomarkers, treatment, outcomes, safety, treatment-monitoring examinations, and registry discontinuation. However, item prioritization reflected local practice, emphasizing diagnostic traceability, functional and neuropsychiatric outcomes, caregiver burden, and structured safety capture. Feasibility results revealed that many MDS elements were collected, but the consensus-defined MDS exceeded what is currently captured in a standardized, analysis-ready format; most EDS items were moderately feasible, while WHO-5 (patient version) and DAT-scan were least feasible.ConclusionsAn InRAD-aligned dataset is broadly acceptable for psychiatry-led AD DMT practices in China, but implementation gaps remain. A phased registry approach with standardized definitions and workflow-supported capture may improve the completeness and comparability of real-world DMT evidence.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261478137"},"PeriodicalIF":3.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148793380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The locus coeruleus gateway hypothesis: Noradrenergic integrity as a candidate determinant of amyloid-β clearance efficiency in anti-amyloid immunotherapy for Alzheimer's disease.","authors":"Charles-Alexandre Dodart","doi":"10.1177/13872877261474020","DOIUrl":"https://doi.org/10.1177/13872877261474020","url":null,"abstract":"<p><p>Anti-amyloid immunotherapies (lecanemab, donanemab) produce statistically significant but clinically modest slowing of decline in early Alzheimer's disease (AD), with substantial inter-individual response variability that current covariates-antibody titer, baseline amyloid load, apolipoprotein E ε4 (<i>APOE4</i>) status, or tau burden-leave largely unexplained. We propose that a systematically unmeasured upstream variable contributes to this variability: the structural integrity of the locus coeruleus (LC), the principal source of brain norepinephrine (NE), framed as a candidate determinant of amyloid-β (Aβ) clearance efficiency rather than of overall clinical outcome. This hypothesis paper synthesizes three peer-reviewed lines of evidence and derives a hierarchy of falsifiable predictions; no new data are reported. First, tau pathology initiates in LC neurons before any cortical structure, reducing NE output from the earliest preclinical stage. Second, NE governs two complementary Aβ-clearance pathways: glymphatic flow, via aquaporin-4 dynamics driven by slow LC oscillations during non-REM sleep, and microglial phagocytosis, via β2-adrenergic receptor signaling. Third, in Parkinson's disease, the DTI-ALPS index mediates the relationship between LC integrity on neuromelanin-sensitive MRI and cognition. We term this the Locus Coeruleus Gateway Hypothesis (LCGH). Its mediation chain is testable now in ADNI, which holds research-grade diffusion-tensor imaging; its treatment-response prediction requires immunotherapy cohorts that acquire such imaging, not the existing CLARITY-AD or TRAILBLAZER-ALZ 2 archives, whose safety MRI used diffusion-weighted, not tensor, sequences. We state explicitly that Aβ clearance is only one contributor to clinical benefit, and that the LCGH predicts pharmacodynamic efficiency, not that NE restoration treats AD.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261474020"},"PeriodicalIF":3.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148793502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between body composition and mortality in older patients with mild cognitive impairment and Alzheimer's disease: NCGG-STORIES.","authors":"Kazuaki Uchida, Taiki Sugimoto, Takeshi Nakagawa, Taiji Noguchi, Ayane Komatsu, Rei Ono, Yoko Yokoyama, Ayaka Onoyama, Takashi Sakurai, Tami Saito","doi":"10.1177/13872877261476079","DOIUrl":"https://doi.org/10.1177/13872877261476079","url":null,"abstract":"<p><p>BackgroundAlthough a lower body mass index (BMI) has been identified as a prognostic risk factor among older adults with cognitive impairment, it remains unclear which body composition are associated with prognosis.ObjectiveThis study investigated the relationship between body composition and mortality in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD).MethodsThis longitudinal study, using data from a memory clinic in Japan, included patients aged ≥65 years who were clinically diagnosed with MCI or AD. Mortality data (date and cause of death) were obtained using a proxy questionnaire. Body composition (muscle mass, fat-free mass, fat mass, %FM) was measured using bioelectrical impedance analysis, and muscle mass index (MMI), fat-free mass index (FFMI) and fat mass index (FMI) were calculated. Body composition index was divided into tertiles (lowest, middle, and highest). To evaluate associations between body composition and mortality, we conducted survival analyses using Cox proportional hazards model (ref. lowest group).ResultsA total of 1575 patients were included in the analysis (mean age, 78.2 years; 63.2% women). The highest FMI and %FM groups had a lower risk of mortality than that in the lowest group (hazard ratio [95% confidence interval]: FMI, 0.55 [0.37-0.81]; %FM, 0.49 [0.33-0.71]), and this association was significant in women with MCI and AD. No significant associations were observed between MMI, FFMI, and mortality.ConclusionsLower FM may be a potential risk factor for poor prognosis, emphasizing the need to monitor it from an early stage of cognitive decline.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261476079"},"PeriodicalIF":3.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of stroke on respiratory function and amyloid-β pathology in Tg-2576 mice.","authors":"Yu-Xing Zhang, Ahmad El Hamamy, Zahid Iqbal, Arya Ranjan, Destiny Sumani, Karienn A De Souza, Juneyoung Lee, Sean Marrelli, Louise D McCullough, Jun Li","doi":"10.1177/13872877261476022","DOIUrl":"https://doi.org/10.1177/13872877261476022","url":null,"abstract":"<p><strong>Background: </strong>Stroke is a well-established risk factor for dementia, and many patients with Alzheimer's disease exhibit mixed neuropathology that includes both ischemic injury and amyloid-β (Aβ) accumulation. Breathing disturbances, such as apnea, have also been linked to cognitive dysfunction and accelerated dementia progression.</p><p><strong>Objective: </strong>We hypothesized that stroke aggravates respiratory dysfunction and cognitive impairment in Tg-2576 mice.</p><p><strong>Methods: </strong>Female Tg-2576 mice (13-17 months old) underwent permanent distal middle cerebral artery occlusion (pd-MCAO), with age- and sex-matched wild-type and sham-operated controls. Cognitive performance was assessed using the Barnes maze. Respiratory parameters were quantified by whole-body plethysmography. Immunofluorescence was performed to measure Aβ deposition in hippocampus and cortex, astrocyte reactivity in retrotrapezoid nucleus (RTN) using GFAP, and LYVE1 in deep cervical lymph nodes (dCLNs). Aβ levels in cerebrospinal fluid were also assessed as a readout related to clearance-associated changes.</p><p><strong>Results: </strong>Compared with wild-type controls, Tg-2576 mice exhibited increased apnea frequency and impaired cognitive performance. Following pd-MCAO, Tg-2576 mice showed a further increase in apnea events and prolonged escape latencies in the Barnes maze. Stroke was also associated with enhanced astrocyte reactivity in the RTN, increased Aβ deposition in the hippocampus and cortex, and reduced Aβ levels in cerebrospinal fluid, along with decreased LYVE1-positive lymphatic area in dCLNs, suggesting compromised glymphatic-lymphatic clearance.</p><p><strong>Conclusions: </strong>Collectively, these findings indicate that stroke worsens respiratory dysfunction, impairs Aβ clearance pathways, and accelerates cognitive decline in Tg-2576 mice. Targeting post-stroke respiratory abnormalities may represent a therapeutic avenue to mitigate dementia-related comorbidity after ischemic injury.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261476022"},"PeriodicalIF":3.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress sensitization: Does childhood adversity modify trauma effects on memory?","authors":"Gina E Nam, Junxian Liu, Mary Thoma, Lindsay C Kobayashi, Karestan C Koenen, Zachary J Kunicki, Eleanor Hayes-Larson","doi":"10.1177/13872877261476095","DOIUrl":"10.1177/13872877261476095","url":null,"abstract":"<p><p>BackgroundTrauma across the lifecourse is implicated in adverse health outcomes, yet whether earlier adversity shapes vulnerability to effects of later trauma on cognitive decline, an important contributor to Alzheimer's disease, remains unclear.ObjectiveWe examined the impact of adult incident traumatic experiences (ITEs) on late-life memory decline, and whether this association is modified by childhood adversity.MethodsWe leveraged 2006-2020 data from the Health and Retirement Study, a longitudinal cohort of US adults aged ≥50 years. ITEs were self-reported stressful or life-threatening experiences in 2006-2012 (any versus none). Childhood adversity (any versus none) included retrospective reports of abuse, neglect, or household dysfunction before age 18. Memory was assessed biennially from 2010-2020 using standardized scores. Linear mixed-effects models estimated associations between ITEs and decline in memory z-score, adjusted for demographics, childhood socioeconomic status, and self-rated health. Stratified analyses examined effect modification by childhood adversity.ResultsAmong 2971 participants, mean baseline age was 67.3 years (SD 9.2); 60% were female and 86% were White. Individuals with ITEs experienced a faster memory decline than those without ITEs (β= -0.014 SD units/year, 95% CI -0.024, -0.003). Childhood adversity did not modify this association. Findings were consistent across sensitivity analyses using alternative exposure and outcome definitions.ConclusionsITEs were associated with accelerated memory decline in later life, and childhood adversity did not modify this relationship. Identifying resilience factors that mitigate the cognitive effects of adult traumatic experiences may inform prevention strategies for Alzheimer's disease.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261476095"},"PeriodicalIF":3.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The case for FDG-PET and NaF-PET in risk stratification of mild cognitive impairment.","authors":"Abass Alavi, Jaskeerat Gujral, Om H Gandhi, Amir A Amanullah, Cyrus Ayubcha, Shiv Patil, Thomas J Werner, Poul Flemming Høilund-Carlsen","doi":"10.1177/13872877261477750","DOIUrl":"https://doi.org/10.1177/13872877261477750","url":null,"abstract":"<p><p>According to a recent study, integrating amyloid-PET, structural MRI, carotid Doppler ultrasound, cognitive testing, and <i>APOE</i> genotyping improves estimation of dementia progression in patients with mild cognitive impairment, with carotid plaque burden emerging as a dominant predictor in amyloid-β-negative cases. We agree that vascular pathology is crucial but suggest that future models consider supplementing amyloid-PET with FDG-PET, a well-validated functional marker of neuronal injury, and carotid Doppler with ¹⁸F-sodium fluoride (NaF)-PET which can detect and quantify early, active microcalcification. This could further improve risk stratification while facilitating detection of potentially modifiable disease processes.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261477750"},"PeriodicalIF":3.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal fluid glial cell line-derived neurotrophic factor levels interact with <i>APOE</i> ε4 genotype to influence cognitive decline in older adults without dementia.","authors":"Shao Wang, Shengzhen Zou","doi":"10.1177/13872877261477047","DOIUrl":"https://doi.org/10.1177/13872877261477047","url":null,"abstract":"<p><p>BackgroundAlthough both apolipoprotein E (<i>APOE</i>) ε4 and glial cell line-derived neurotrophic factor (GDNF) are implicated in the pathogenesis of Alzheimer's disease (AD), it remains unclear whether they interact to affect cognitive decline among older adults without dementia.ObjectiveThis study aimed to examine the interactive effects of <i>APOE</i> ε4 and GDNF on longitudinal cognitive decline.MethodsA total of 543 individuals (mean age 73 [±7] years; 43% female) with cognitively unimpaired (CU) or mild cognitive impairment (MCI) were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear mixed-effects models were used to examine the contributions of cerebrospinal fluid (CSF) GDNF levels and <i>APOE</i> ε4 status to longitudinal changes in cognitive measures, including the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating - Sum of Boxes (CDR-SB), the 13-item Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog-13), and the Rey Auditory Verbal Learning Test (RAVLT) total score.ResultsWe found that the 3-way interaction (<i>APOE</i> ε4 × GDNF × time) was significant for MMSE, CDR-SB, and ADAS-Cog-13, and of marginal significance for RAVLT total score, after adjusting for age, sex, and education. Specifically, individuals who were <i>APOE</i> ε4 carriers with low CSF GDNF levels showed the fastest rate of cognitive decline among the four groups (Low/<i>APOE4</i>-, High/<i>APOE4</i>-, Low/<i>APOE4</i>+, and High/<i>APOE4</i>+).Conclusions<i>APOE</i> ε4 appears to interact with CSF GDNF levels to affect longitudinal cognitive decline among older adults without dementia.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261477047"},"PeriodicalIF":3.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}