Frontiers in Aging Neuroscience最新文献

{"title":"Reproductive life stages and cognitive outcomes: a systematic review in Latin American and Caribbean women.","authors":"Nickole Marín-Díaz, Sofia Binetti, Jaime Cañas, Carolina Panesso, Javier Villacreses, Paulina Orellana, Carolina Gonzalez-Silva, Josefina Cruzat, Joaquín Migeot, Paola Murgas, Hernán Hernández, Martin Bruno, Nilton Custodio, Rosa Montesinos, José Alberto Avila-Funes, Diana Matallana, Hernando Santamaria-García, Natalia Vilor-Tejedor, Federica Anastasi, Shireen Sindi, Andrea Slachevsky, J E Blümel, Sidra Sohail, Melissa Marquez, Grace E Bardwick, Ana W Capuano, Agustín Ibañez, Francesca R Farina, Claudia Duran-Aniotz","doi":"10.3389/fnagi.2026.1826530","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1826530","url":null,"abstract":"<p><p>Reproductive life stages, menopausal symptoms, and hormonal exposures are increasingly recognized as potential determinants of cognitive outcomes in women. However, these associations remain largely understudied in Latin American and Caribbean (LAC) populations. In this systematic review, we identified 18 observational studies published between 2003 and 2025. Of these, 16 were conducted across 13 LAC countries and two were conducted among latina women in the United States. Evidence was organized across four reproductive life stages domains: reproductive history, menopausal hormone therapy use, type of menopause and menopausal symptoms, and postmenopausal factors. Most LAC studies were cross-sectional and demonstrated substantial methodological heterogeneity. Across studies, shorter reproductive span, earlier menopause, higher parity, surgical menopause, and greater menopausal symptom burden were generally associated with poorer cognitive performance or higher odds of mild cognitive impairment. Some studies suggested favorable associations between menopausal hormone therapy use and cognitive outcomes. Postmenopausal factors, such as sarcopenia and obesity, as well as a longer duration of menopause, were predominantly linked to poorer cognitive outcomes. Only one population-based cohort evaluated incident dementia, underscoring the scarcity of longitudinal evidence in the region. Overall, the evidence suggests that reproductive life stages in LAC women are meaningfully associated with cognitive outcomes, reflecting the influence of hormonal transitions, menopausal characteristics, and postmenopausal health within distinctive regional contexts. However, the predominance of cross-sectional designs and limited regional representativity, coupled with a lack of integrated physiological indicators, reveal a substantial knowledge gap. Longitudinal and regionally representative cohorts incorporating standardized assessments of reproductive life stages alongside comprehensive cognitive measures are essential to understanding how reproductive life stages shape cognitive outcomes in LAC women. <b>Systematic review registration</b>: The systematic review was registered in the Open Science Framework (OSF). Registration DOI/unique identifier: https://doi.org/10.17605/OSF.IO/ME7XK.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1826530"},"PeriodicalIF":5.2,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-group differences in diffusion MRI characteristics of cortico-cerebellar tracts and their association with bimanual performance.","authors":"Maud Beeckmans, Shanti Van Malderen, Sara Magalhães Ferreira, Melina Hehl, Louise Emsell, Stefan Sunaert, Ahmed Radwan, Koen Cuypers","doi":"10.3389/fnagi.2026.1933331","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1933331","url":null,"abstract":"<p><strong>Introduction: </strong>Aging is associated with alterations in white matter structure and decline in bimanual performance. These parallel changes may be interrelated, as previous studies have linked cerebral white matter properties to both motor and cognitive function. The cerebellum plays a central role in complex motor coordination and higher-order processes, yet age-related differences in cortico-cerebellar pathways remain insufficiently understood. This study therefore examined two major cortico-cerebellar tracts - the dentato-rubro-thalamo-cortical tract (DRTT) and the cortico-ponto-cerebellar tract (CPCT) - to assess age-related differences in white matter properties and their association with bimanual motor performance.</p><p><strong>Methods: </strong>Diffusion Magnetic Resonance Imaging data from 46 younger and 46 older healthy adults were analyzed using a state-of-the-art fixel-based analysis approach to derive fiber-specific metrics reflecting micro- and macrostructural axonal properties.</p><p><strong>Results: </strong>An overall reduction in fiber density and cross-section was observed in older adults, primarily driven by macrostructural differences; alongside localized increases in these structural properties in specific regions. No significant associations were found between cortico-cerebellar white matter properties and bimanual motor performance.</p><p><strong>Discussion: </strong>These findings corroborate the general patterns of age-related white matter decline while underscoring the importance of within-tract analyses. Although cortico-cerebellar pathways demonstrate age-related structural differences, their contribution to age-related alterations in bimanual coordination performance in healthy aging may be limited or obscured by tract-level averaging masking regional effects and the multifactorial nature of bimanual motor coordination, which reflects the interaction of distributed neural and peripheral systems. The observed regional increases of fiber-specific measures in older adults may reflect age-related adaptations. Yet, their functional significance remains uncertain and warrants further investigation.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1933331"},"PeriodicalIF":5.2,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gait performance in cerebral small vessel disease: associations with cognitive and oculomotor function and exploratory mediation analyses.","authors":"Chen-Xin Shen, Xiao-Ying Zhao, Shi-Yao Wang, Yan-Wei Miao, Zhan-Hua Liang, Lin Liu, Bing-Wei Zhang","doi":"10.3389/fnagi.2026.1935861","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1935861","url":null,"abstract":"<p><strong>Background: </strong>Gait impairment in cerebral small vessel disease (CSVD) is heterogeneous and may not be fully explained by conventional structural MRI markers. We investigated the associations of neuroimaging burden, cognitive function, and oculomotor function with gait performance in CSVD and explored potential indirect associations between CSVD burden and gait impairment.</p><p><strong>Methods: </strong>We included 65 individuals with CSVD and 35 control participants. All participants underwent quantitative gait assessment, standardized neuropsychological evaluation, and oculomotor recording. Patients with and without gait disorder were compared after adjustment for the total CSVD load score. Correlation analyses assessed associations among neuroimaging markers, cognitive and oculomotor measures, and gait parameters. Exploratory mediation analyses examined cognitive and oculomotor measures as potential statistical indirect pathways between total CSVD load and gait performance.</p><p><strong>Results: </strong>Compared with control participants, patients with CSVD had poorer gait, cognitive, and oculomotor performance (<i>P</i> < 0.05). Despite comparable total CSVD load, patients with gait disorder showed worse executive function and visuospatial ability, prolonged saccade latency, reduced fixation stability, and lower anti-saccade accuracy (FDR-adjusted <i>P</i> < 0.05). Total CSVD load and perivascular spaces (PVS) burden were associated with cognitive, gait, and oculomotor measures. In the exploratory mediation analyses, Trail Making Test-B performance showed a significant indirect association between total CSVD load and gait impairment, with no significant residual direct association. Trail Making Test-A performance, fixation stability, and saccade latency, also showed significant indirect association, while the corresponding direct associations remained significant.</p><p><strong>Conclusions: </strong>Executive and oculomotor dysfunction were associated with gait impairment in CSVD and may partly account for the association between total CSVD burden and gait performance. These exploratory findings require confirmation in larger longitudinal studies.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1935861"},"PeriodicalIF":5.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hybrid multimodal late fusion frameworks for bvFTD classification in imbalanced dementia datasets.","authors":"Majid Ramedani, Jaya C Terli, Devesh Singh, Oliver Peters, Julian Hellmann-Regen, Josef Priller, Eike Jakob Spruth, Annika Spottke, Anne Boehlen, Patrick Weydt, Ullrich Wüllner, Elisabeth Dinter, Rene Günther, Jens Wiltfang, Björn H Schott, Emrah Düzel, Wenzel Glanz, Katharina Buerger, Daniel Janowitz, Johannes Levin, Anna Stockbauer, Mihovil Mladinov, Johannes Prudlo, Andreas Hermann, Matthis Synofzik, David Mengel, Gabor C Petzold, Anja Schneider, Falk Lüsebrink, Stefan Hetzer, Peter Dechent, Michael Ewers, Klaus Scheffler, Sophia Stöcklein, Stefan Teipel, Martin Dyrba","doi":"10.3389/fnagi.2026.1892568","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1892568","url":null,"abstract":"<p><strong>Background: </strong>Behavioral variant frontotemporal dementia (bvFTD) is an irreversible neurodegenerative disorder characterized by progressive changes in personality and behavior. Magnetic Resonance Imaging (MRI) is widely used to detect and assess structural brain alterations associated with the disease. However, due to the low prevalence of bvFTD among neurodegenerative diseases causing the dementia syndrome, conventional machine learning approaches may struggle to capture comprehensive feature representations. Therefore, this study proposes two late fusion frameworks that integrate a 3D convolutional neural network and a multilayer perceptron (MLP) for improved bvFTD diagnosis.</p><p><strong>Methods: </strong>A total of 5,928 participants were included, comprising 3,415 healthy controls (HC), 2,276 Alzheimer's disease (AD), and 237 bvFTD, resulting in a class imbalanced setting with bvFTD as the minority class. To address class imbalance, bvFTD data were initially augmented. A 3D-DenseNet was used to extract features from 3D T1-weighted MRI scans, while an MLP-based model was applied to regional brain volumetric measurements obtained from automated MRI-based brain segmentation. Twelve CNN models with different hyperparameter configurations were trained. Models with and without data augmentation, as well as two fusion-based approaches, were evaluated using accuracy, F1-score, and area under the curve (AUC).</p><p><strong>Results: </strong>Both fusion strategies improved accuracy, F1-score, and AUC compared to the baseline model without data augmentation. Notable improvement was also observed for the bvFTD class, with up to a 120% increase in F1-score. In one of the fusion frameworks, an accuracy of 0.95 ± 0.01 was achieved for bvFTD vs. HC classification. The results demonstrate the effectiveness of the fusion-based approaches compared to non-fused models, outperforming several state-of-the-art methods.</p><p><strong>Conclusion: </strong>The proposed frameworks demonstrate that data augmentation and fusion strategies can improve accuracy, F1-score, and AUC, with statistically significant gains. Overall, the frameworks improve diagnostic performance and support the identification of relevant biomarkers associated with bvFTD pathology.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1892568"},"PeriodicalIF":5.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil-to-lymphocyte ratio predicts early cognitive decline associated with tau pathology in Alzheimer's disease: a longitudinal study of the ADNI cohort.","authors":"Xin Wang, Xiaolei Liu, Zhigang Wang, Chenle Jia","doi":"10.3389/fnagi.2026.1872617","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1872617","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation is a key driver of Alzheimer's disease (AD). Although the neutrophil-to-lymphocyte ratio (NLR) is an easily accessible peripheral inflammatory marker, yet its longitudinal association with domain-specific cognitive decline and the underlying neuropathological mechanisms during the preclinical and early stages of AD remain unclear.</p><p><strong>Methods: </strong>A total of 1,190 non-people living with dementia older adults from the AD Neuroimaging Initiative cohort were included, comprising 405 cognitively normal participants and 785 participants with mild cognitive impairment (MCI). Participants were stratified according to baseline NLR (≥ 3versus < 3). Linear mixed-effects models were used to examined the association between baseline NLR and longitudinal decline across multiple cognitive domains. Cox proportional hazards model assessed progression risk to MCI or AD. Mediation analyses evaluated whether cerebrospinal fluid (CSF) biomarkers, including amyloid-β₄₂ (Aβ₄₂), total tau (t-tau), and phosphorylated tau (p-tau), statistically accounted for the association between NLR and cognitive decline.</p><p><strong>Results: </strong>During follow-up, a high baseline NLR (≥ 3) was independently associated with accelerated decline in global cognition, memory, executive function, language, and visuospatial abilities (all <i>p</i> < 0.05), as well as a 20% higher risk of clinical progression per 1-unit increase in NLR (hazard ratio = 1.20, 95% confidence interval: 1.12-1.29, <i>p</i> = 0.001). Mediation analyses indicated that CSF t-tau and p-tau, but not Aβ₄₂, partially explained the association between NLR and cognitive decline. The observed associations remained robust across sensitivity and subgroup analyses.</p><p><strong>Conclusion: </strong>Elevated NLR was significantly and independently associated with accelerated decline across multiple cognitive domains and an increased risk of clinical progression in older adults at risk for AD. The observed associations with tau pathology are consistent with a potential role for peripheral immune dysregulation in early disease trajectories; however, formal predictive modeling and external validation are required before clinical application.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1872617"},"PeriodicalIF":5.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence for white matter hyperintensity segmentation: performance, determinants, and clinical implications.","authors":"Jinhua Hu, Zhihao Zhang, Peng Lei, Jupeng Zhang, Xiqi Zhu, Baosheng Li","doi":"10.3389/fnagi.2026.1930675","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1930675","url":null,"abstract":"<p><strong>Objective: </strong>White matter hyperintensities (WMH) are key neuroimaging markers of cerebral small vessel disease, associated with cognitive decline and stroke risk. Accurate quantification is essential yet manual segmentation is time-consuming and variable. We systematically evaluated AI performance for automated WMH segmentation across disease contexts and identified factors influencing model performance.</p><p><strong>Methods: </strong>Following PRISMA guidelines, we searched PubMed, Embase, Web of Science, Scopus, and IEEE Xplore from database inception to February 3, 2026 (PROSPERO: CRD420261355769). Studies employing AI-based WMH segmentation and reporting Dice similarity coefficient (DSC) were included. A random-effects meta-analysis was conducted, along with subgroup analyses, meta-regression, sensitivity analyses, and publication bias assessment.</p><p><strong>Results: </strong>26 studies comprising 4,288 participants contributed to quantitative syntheses: 13 evaluated WMH segmentation in general cohorts, and 13 evaluated AD or CSVD-specific cohorts. In the general cohort meta-analysis, the pooled DSC was 0.78 (95% CI, 0.74-0.82). Disease-specific pooled DSC estimates were 0.75 for AD and 0.78 for CSVD. Exploratory meta-regression suggested an association between scanning parameters and DSC (<i>p</i> = 0.042), whereas magnetic field strength showed a borderline association (<i>p</i> = 0.052).</p><p><strong>Conclusion: </strong>AI demonstrates promising performance for automated WMH segmentation, with U-Net-based architectures showing superior accuracy. However, substantial heterogeneity highlights the need for standardized imaging protocols and robust external validation. Future multicenter studies are essential to improve model generalizability and facilitate clinical translation.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1930675"},"PeriodicalIF":5.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging on the road: neural and behavioral correlates of cognitive control during distracted driving.","authors":"Emad Alyan, Stephan Getzmann, Edmund Wascher, Melanie Karthaus","doi":"10.3389/fnagi.2026.1864407","DOIUrl":"10.3389/fnagi.2026.1864407","url":null,"abstract":"<p><strong>Objective: </strong>Aging increases crash risk through failures to prioritize safety-critical actions amid competing information. The neural basis of adaptive cognitive control under these demands remains insufficiently understood.</p><p><strong>Methods: </strong>This study examined age effects on braking prioritization in 44 drivers (23 younger, 21 older) using a car-following simulation with lane keeping, in which participants withheld sign responses whenever brake signals took priority. Participants completed Sign (button press to classify road signs), Brake (pedal press to the brake lights of the car ahead), and dual-demand signBrake trials (simultaneous Sign and Brake, braking prioritized). Measures included reaction time, errors, mean absolute steering-wheel angle, blink metrics, ERPs (N1, P3, and LFN), time-frequency power, and multivariate pattern analysis (MVPA) of age decoding.</p><p><strong>Results: </strong>Older adults exhibited selective signBrake costs, with slower and less accurate braking than younger adults, and a larger mean absolute steering-wheel angle. In both groups, steering-wheel angle decreased from the pre- to the post-stimulus period, with the largest drop in signBrake. Blink rate did not differ by age, but younger adults exhibited longer blink durations and larger amplitude-velocity ratios, suggesting differences in how blinks punctuate attentional sampling during driving. The LFN (late frontal negativity), a preparatory index of response control, showed weaker condition-related differentiation in older adults, who also exhibited larger N1 but smaller P3 amplitudes. This pattern fits greater early visual attentional selection and weaker later evaluation and context updating. Time-frequency analyses revealed reduced frontal theta, parietal alpha, and central beta power in older adults across conditions. Central beta demonstrated the strongest Age × Condition modulation, driven mainly by older adults, while younger adults showed no reliable condition differences, which fits weaker post-stimulus attentional gating and altered sensorimotor tuning during action selection. MVPA decoded age group above chance after stimulus onset in all three conditions. Cross-condition decoding succeeded across train-test pairings, consistent with a distributed age-related neural signature that generalizes across contexts.</p><p><strong>Conclusion: </strong>These findings tie signBrake performance costs to weaker preparatory control differentiation and altered post-stimulus dynamics that support braking under interference. This reduced flexibility may contribute to age-related declines in driving safety in moments that call for rapid, goal-directed control.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1864407"},"PeriodicalIF":5.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal patterns of regional cerebral blood flow during anti-amyloid therapy in mild cognitive impairment: a pilot ASL MRI case series.","authors":"Eva Y W Cheung, Yat Fung Shea, Patrick K C Chiu, Koon Ho Chan, Hui Zhang, Ka Keung Yam, Kyongtae T Bae, Henry K F Mak","doi":"10.3389/fnagi.2026.1903239","DOIUrl":"10.3389/fnagi.2026.1903239","url":null,"abstract":"<p><strong>Introduction: </strong>The neurovascular effects of anti-amyloid therapy remain incompletely understood. Arterial spin labeling (ASL) MRI enables non-invasive quantification of regional cerebral blood flow (rCBF) and may provide insight into perfusion patterns observed over the treatment period.</p><p><strong>Methods: </strong>This pilot observational case series included participants with MCI or very early Alzheimer's disease undergoing anti-amyloid therapy (lecanemab), who underwent longitudinal pseudo-continuous ASL MRI at baseline and predefined follow-up timepoints. Regional rCBF was quantified across predefined cortical and subcortical regions of interest. A comparison group of amyloid-positive participants with MCI who did not receive anti-amyloid therapy underwent baseline ASL MRI. Vascular and metabolic risk factors, including white matter hyperintensity burden and biochemical parameters, were assessed to characterize potential confounding influences.</p><p><strong>Results: </strong>Within the treated group, increased rCBF was observed at early follow-up in several frontal, sensorimotor, and subcortical regions. No statistically significant longitudinal changes were detected at intermediate follow-up. At later follow-up, increased rCBF was observed in the cerebellar cortex, while decreased rCBF was observed in bilateral medial temporal regions. Vascular and metabolic risk profiles, including WMH burden, were broadly comparable between groups.</p><p><strong>Discussion: </strong>The observed rCBF trajectories demonstrate region-specific and time-dependent perfusion changes over the treatment period. Given the small sample size, absence of longitudinal imaging in the control group, and residual vascular confounding, these findings should be interpreted cautiously as exploratory and hypothesis-generating rather than evidence of treatment efficacy.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1903239"},"PeriodicalIF":5.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term risk of incident dementia following documented COVID-19 among older adults with type 2 diabetes: a propensity score-matched cohort study.","authors":"I-Wen Chen, Li-Chen Chang, Chun-Ning Ho, Kuo-Chuan Hung","doi":"10.3389/fnagi.2026.1927383","DOIUrl":"10.3389/fnagi.2026.1927383","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes mellitus (T2DM) is a well-established risk factor for dementia, and COVID-19 has been associated with persistent neurological and cognitive sequelae. However, whether this association extends beyond the early post-infection period among older adults with T2DM-a population with compounded vascular and metabolic vulnerability-remains unclear.</p><p><strong>Methods: </strong>Using the TriNetX Global Collaborative Network, we conducted a retrospective cohort study of patients aged ≥65 years with T2DM, comparing those with documented COVID-19 to a matched unexposed cohort (1:1 propensity score matching). A 1-year landmark design was applied, with follow-up extending to 6 years after the index date. The primary outcome was incident overall dementia, which is a composite of vascular dementia, Alzheimer's disease, and unspecified/other dementia. The secondary outcomes included individual dementia subtypes, mild cognitive impairment, all-cause mortality, and cerebral infarction.</p><p><strong>Results: </strong>After matching, 449,745 patients were included in each group with well-balanced covariates (all standardized mean differences <0.1). Documented COVID-19 was associated with a significantly increased risk of overall dementia [hazard ratio (HR 1.51), 95% confidence interval (CI) 1.47-1.55, <i>p</i> < 0.001]. The secondary outcomes were similarly elevated, such as vascular dementia (HR 1.61), Alzheimer's disease (HR 1.41), mild cognitive impairment (HR 1.66), all-cause mortality (HR 1.56), and cerebral infarction (HR 1.33; all <i>p</i> < 0.001). The hazard ratio for overall dementia increased progressively across sequential landmark periods (1.51 at 1 year, 1.66 at 2 years, and 2.09 at 3 years), and the findings remained robust across sensitivity analyses, addressing survival, healthcare utilization, and exposure misclassification. The findings were consistent in separately constructed and propensity score-matched additional cohorts restricted to adults aged 50-65 years and to patients indexed during the Omicron-predominant period.</p><p><strong>Conclusion: </strong>In this large propensity score-matched cohort study, documented COVID-19 was associated with an increased long-term risk of incident dementia among older adults with T2DM, with the association persisting and strengthening beyond the early post-infection period. These findings support sustained attention to cognitive health in this metabolically susceptible population following COVID-19; however prospective studies incorporating standardized cognitive and biomarker assessments are needed to clarify underlying causes.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1927383"},"PeriodicalIF":5.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AAV-mediated gene therapy for Alzheimer's disease: neuroprotective mechanisms and translational challenges.","authors":"Zehua Yu, Yang Li, Zeyu Zhang, Rong Yin","doi":"10.3389/fnagi.2026.1901875","DOIUrl":"10.3389/fnagi.2026.1901875","url":null,"abstract":"<p><p>Alzheimer's disease remains a major neurodegenerative disorder for which effective disease-modifying treatments are limited. Adeno-associated virus-mediated gene therapy provides a strategy for sustained modulation of disease-related pathways in the central nervous system. Recent studies have explored this approach for regulating amyloid-β (Aβ) metabolism, tau pathology, neuroinflammation, genetic risk factors and neurotrophic support. This review summarizes the biological basis for adeno-associated virus delivery in the central nervous system and discusses major therapeutic strategies for Alzheimer's disease, including approaches targeting Aβ production and clearance, tau expression and degradation, immune microenvironment remodeling, apolipoprotein E modulation and synaptic protection. We further examine key translational barriers, including blood-brain barrier restriction, cross-species differences, immune responses, dose-related toxicity, manufacturing constraints and limited clinical evidence. Finally, we propose that future development should move beyond delivery efficiency alone toward biologically informed vector design, target selection, disease-stage matching and biomarker-guided clinical evaluation.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1901875"},"PeriodicalIF":5.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}