Aging brain最新文献

{"title":"Spatial patterns of Wnt/β-catenin signaling in the adult and aging Nothobranchius furzeri brain","authors":"Emily Whisenant,&nbsp;Arne Lekven","doi":"10.1016/j.nbas.2026.100170","DOIUrl":"10.1016/j.nbas.2026.100170","url":null,"abstract":"<div><div>Age-related neurodegenerative diseases are a growing health concern, yet the molecular mechanisms driving neural decline remain poorly understood. The canonical Wnt/β-catenin signaling pathway regulates key aspects of neural development and adult brain homeostasis, and its dysregulation is implicated in aging. However, its spatial and temporal regulation in the aging brain is not fully characterized. The African turquoise killifish (<em>Nothobranchius furzeri</em>), with its short lifespan and conserved aging features, offers a valuable model for studying brain aging. Using <em>N. furzeri</em> as a model, we generated two novel Wnt signaling transgenic lines to track Wnt signaling: <em>Tg(Sp5a:eGFP)</em> and <em>Tg(7xTCF:mCherry)</em>. We characterized their expression pattern, as well as the endogenous expression of several Wnt-related targets, throughout different regions in the adult brain. We found that there was overlapping expression in both reporters throughout much of the brain, but divergent expression particularly in the habenula and fasciculus retroflexus. Additionally, we examined how this pattern of Wnt activity changed throughout aging in both whole brains and isolated brain regions. We found that there were no significant changes across the whole-brain level; however, there were visible, sex-specific structural changes in the fasciculus retroflexus and alterations in Wnt target transcripts, <em>axin2</em> and <em>sp5</em>, in the mesencephalon. Taken together, these results demonstrate region- and sex-specific regulation of Wnt signaling in the aging <em>N. furzeri</em> brain.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"10 ","pages":"Article 100170"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased functional integration of emotional control network across the adult lifespan","authors":"Leona Rahel Bätz,&nbsp;Shuer Ye,&nbsp;Melissa Schubbert,&nbsp;Xiaqing Lan,&nbsp;Maryam Ziaei","doi":"10.1016/j.nbas.2026.100156","DOIUrl":"10.1016/j.nbas.2026.100156","url":null,"abstract":"<div><div>Emotional well-being has often been shown to improve across the adult lifespan. The corresponding effects, however, in the emotion regulation brain networks remain underexplored. By utilizing large-scale datasets such as the Human Connectome Project (HCP-Aging, N = 621, 349 females) and Cambridge Centre for Ageing and Neuroscience (Cam-CAN, N = 333, 155 females), we were able to investigate how emotion regulation networks’ functional topography differs across the entire adult lifespan. Based on previous <em>meta</em>-analytic work that identified four large-scale functional brain networks involved in emotion generation and regulation, we investigated the association between the integration of these emotion regulation networks and measures of mental well-being with age in the HCP-Aging dataset. We found an increased functional integration of the emotional control network among older adults, which was replicated using the Cam-CAN dataset. Further we found that the interoceptive network, which is mediating emotion generative and regulative processes and carries our introspective and reflective functions, is less integrated in higher age. Our study highlights the importance of identifying topological changes in the functional emotion network architecture across the lifespan, as it allows for a better understanding of functional brain network alterations that accompany emotional aging.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"9 ","pages":"Article 100156"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379709","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":"Effects of aerobic exercise intervention on the association between brain functional connectivity and cognition among older adults","authors":"Myungjin Jung,&nbsp;Marco Pipoly,&nbsp;Bryan Madero,&nbsp;Chris Oehler,&nbsp;Kelsey Baller,&nbsp;Vincent A. Magnotta,&nbsp;Jeffrey D. Long,&nbsp;Gary L. Pierce,&nbsp;Michelle W. Voss","doi":"10.1016/j.nbas.2026.100162","DOIUrl":"10.1016/j.nbas.2026.100162","url":null,"abstract":"<div><div>Chronic aerobic exercise is known to protect against brain and cognitive aging in animals, but it remains unclear whether these benefits are consistent across the span of older adulthood. Using time-varying effect modeling (TVEM) analysis, this study investigated how the associations between changes in cognition and brain network functional connectivity (FC), induced by a 6-month aerobic exercise intervention, vary with age among older adults aged 55 to 80 (<em>n</em> = 107). Participants were divided into two groups based on exercise intensity: moderate-to-vigorous (ModVig group) and light-intensity (Light group). Before and after the intervention, participants completed cognitive tasks measuring executive function (EF) and processing speed (PS) and underwent resting-state fMRI sessions. FC was assessed across large-scale brain networks, including the frontoparietal control (FPCN), default mode (DMN), dorsal attention (DAN), limbic (LN), salience (SN), somatomotor (SMN), and visual network (VN). Change scores for each cognitive task and FC network were calculated by subtracting pre-intervention scores from post-intervention scores. Older adults in the ModVig group demonstrated improved PS performance at ages 58 to 65 and increased FC at ages 67 to 69 in the DAN. When individuals were exposed to ModVig intensity exercise, increases in FC within the FPCN, DMN, and SN were associated with improved EF and PS performance in those in their mid-60s to mid-70s. These findings support the importance of targeting higher moderate-to-vigorous aerobic exercise intensity for interventions, particularly in this age group, to enhance brain and cognitive health.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"10 ","pages":"Article 100162"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148644667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-related differences in asymmetric synapses across the central inferior colliculus in the Fischer Brown Norway rat","authors":"Gillian L. Barach ,&nbsp;Alexa Wawrzyniak ,&nbsp;Justine Busby ,&nbsp;Syllissa Duncan ,&nbsp;Laila S. Almassri ,&nbsp;Amir Mafi ,&nbsp;Nick J. Tokar ,&nbsp;Marina A. Silveira ,&nbsp;Jesse W. Young ,&nbsp;Jeffrey G. Mellott","doi":"10.1016/j.nbas.2026.100158","DOIUrl":"10.1016/j.nbas.2026.100158","url":null,"abstract":"<div><div>The rapidly aging populations of industrial countries are commonly affected by age-related hearing loss (ARHL). A broad mechanistic theme to ARHL are imbalances to excitation and inhibition in the central auditory system in response to the reduced excitatory cochlear input. Many studies on these imbalances have focused on the changes to inhibitory/GABAergic neurotransmission in the lemniscal central inferior colliculus (ICc), leading to the poor temporal processing that characterizes ARHL. One of our recent studies demonstrated that GABAergic synapses across the ICc were downregulated in a non-uniform manner. We therefore sought to determine if presumptively excitatory asymmetric synapses were also downregulated in the same non-uniform manner. We used electron microscopy (EM) and post-embedding anti-GABA immunogold histochemistry across four age groups (3-month, 19-month, 24-month, and 28-month) of Fischer Brown Norway rats to examine the ultrastructure of asymmetric synapses in the IC. Presumptively excitatory asymmetric synapses were identified by asymmetric synaptic junctions, round vesicles, and GABA-immunonegative presynaptic boutons. Our data were collected across the dorsolateral to ventromedial axis of the ICc. Our primary result is that there is a significant downregulation (∼30%) of asymmetric synapses starting in late middle-age that occurs largely in a uniform manner across the dorsolateral-ventromedial axis of the ICc. Unlike our previous study on the downregulation of GABAergic synapses in the ICc, asymmetric synapses are downregulated across the ICc axis in a more uniform manner. These data demonstrate that there is a broad and robust loss of excitatory inputs throughout the ICc.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"9 ","pages":"Article 100158"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147749699","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":"Acute normobaric hypoxia as a reversible probe of oxygen-limitation contributions to cognitive aging","authors":"Pierrick Laulan","doi":"10.1016/j.nbas.2026.100161","DOIUrl":"10.1016/j.nbas.2026.100161","url":null,"abstract":"<div><div>Chronological age cannot be experimentally manipulated, which limits causal tests of candidate mechanisms in cognitive aging. This focused review evaluates acute, dose-controlled normobaric hypoxia as a reversible probe of whether oxygen-delivery and cerebrovascular-reserve constraints contribute to age-sensitive cognitive phenotypes, particularly associative episodic memory. Evidence from cognitive hypoxia, cerebrovascular aging, and cerebral oxygenation suggests acute hypoxia and later-life cerebrovascular compromise share common mechanisms that reduce the capacity to meet increased neural metabolic demands during high-load cognitive tasks. Associative memory is proposed as a particularly informative target phenotype because it is reliably vulnerable in aging, strongly dependent on hippocampal binding, and theoretically dissociable from more global performance decrements. Emotional effects are considered only insofar as arousal and sustained stress can modify associative binding, with acute hypoxia framed as imposing conditions of vulnerability under sustained and unavoidable stress rather than reproducing age-related positivity. Four conditions are then identified for informative oxygen-limitation inference: dose and capnic (arterial or end-tidal carbon dioxide) characterization, phenotype-specific dissociation tests, coupling to oxygen-sensitive markers, and discriminant validity against non-specific changes in stress, discomfort, or fatigue. Acute normobaric hypoxia is therefore presented as a reversible causal probe, not as a model of aging; its value depends on stringent boundary conditions and careful mechanistic interpretation.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"10 ","pages":"Article 100161"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148531973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomic analysis reveals age-related remodeling of brain endothelial cells","authors":"Hai Duc Nguyen,&nbsp;Summer Siddiqui,&nbsp;Diana G. Bohannon,&nbsp;Robert V. Blair,&nbsp;Hong-Wen Deng,&nbsp;Alexandre Prat,&nbsp;Woong-Ki Kim","doi":"10.1016/j.nbas.2026.100164","DOIUrl":"10.1016/j.nbas.2026.100164","url":null,"abstract":"<div><div>Blood–brain barrier (BBB) integrity naturally declines with age. Brain endothelial cells (ECs) and pericytes (PCs) form the BBB, and aging impairs tight junctions, likely via altered PC-to-EC signaling. However, the molecular mechanisms underlying this impairment remain unclear. Using single-cell RNA sequencing, we profiled 68,316 brain ECs expressing 15,564 genes from young and old mice. Unsupervised clustering and annotation revealed five distinct EC subtypes—Capillary EC1, Capillary EC2, Arterial EC, Venous EC1, and Venous EC2—defined by marker genes <em>Mfsd2a, Plvap, Bmx, Nr2f2</em>, and <em>Vcam1</em>, respectively. Aging shifted EC subtype distribution, with reduced Capillary EC1 (45% vs. 57%) and increased Arterial (33% vs. 16%) and Venous ECs (12% vs. 2%) compared with young mice. Mio analysis further showed that Capillary EC1 and Venous EC2 neighborhoods were less abundant in aged brains. Biotin metabolism was decreased in old vs. young mice, particularly within Capillary EC1, Capillary EC2, and Arterial EC. Although widespread gene downregulation was observed across EC subsets, overall expression trends were largely consistent among clusters. Key genes—<em>Ramp2, Hbb-bs, Ly6c1, Calm1</em>—were less abundant, whereas <em>Rasgrf2</em> was uniquely enriched in aged mice. Immunohistochemistry confirmed reduced LY6C and RAMP2 and elevated RASGRF2 in aged mouse and human brains. Cell–cell interaction analyses revealed age-associated remodeling of ligand-receptor signaling. Enrichment analyses implicated pathways involved in neurovascular integrity, inflammation, amyloid processing, and vascular remodeling. Collectively, these findings show that aging reprograms EC subtype composition, gene expression, and metabolism, thereby contributing to BBB disruption and neurovascular dysfunction.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"10 ","pages":"Article 100164"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148644666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Change in brain glucose metabolism and cognition in amnestic MCI patients in relation to amyloid accumulation: A 3-year follow-up study","authors":"Elina Rauhala,&nbsp;Jarkko Johansson,&nbsp;Mira Karrasch,&nbsp;Olli Eskola,&nbsp;Tuula Tolvanen,&nbsp;Johan Rajander,&nbsp;Juha O. Rinne","doi":"10.1016/j.nbas.2026.100165","DOIUrl":"10.1016/j.nbas.2026.100165","url":null,"abstract":"<div><div>Our aim was to investigate the change in brain glucose metabolism with [¹⁸F]fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG PET) in amyloid beta positive and negative amnestic mild cognitive impairment (aMCI) patients. We investigated associations between change in [¹⁸F]FDG uptake and cognitive functioning in aMCI patients over up to 3 years. Twenty patients underwent [¹⁸F]FDG PET (15 men and 5 women, mean age 73.0 years, SD 6.3 at baseline) within a short time interval from [¹⁸F]Flutemetamol PET. The patients were classified as amyloid positive vs. negative based on the amyloid PET marker [¹⁸F]Flutemetamol uptake. Patients were examined with brain MRI and cognitive tests at baseline and after 3-year follow-up or earlier if the patient had converted to probable Alzheimer's disease. [¹⁸F]FDG data was analysed with automated region-of-interest analysis and voxel-based statistical parametric mapping (SPM). [¹⁸F]FDG uptake nor change of [¹⁸F]FDG uptake over time differed between amyloid positive and negative groups. However, the amyloid positive patients exhibited significant decline in MMSE scores over three years while the amyloid negative patients maintained stable MMSE level over time. The amyloid positive group had poorer episodic memory scores at baseline and follow-up, and significantly slower processing speed at follow-up as well as significantly more negative change over time in language functions compared to amyloid negative patients. Moreover, we found that [¹⁸F]FDG uptake was positively associated with cognition in the whole aMCI patient group. Together, our results suggest that brain glucose metabolism in aMCI is independent of amyloid pathology, and probably reflects other brain degenerative processes.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"10 ","pages":"Article 100165"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148741070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between subjective cognitive concern, brain network connectivity, and cognitive performance in cognitively normal older adults","authors":"Kimberly Albert ,&nbsp;Brian Boyd ,&nbsp;Brenna McDonald ,&nbsp;Julie Dumas ,&nbsp;Andrew Saykin ,&nbsp;Warren Taylor ,&nbsp;Paul Newhouse","doi":"10.1016/j.nbas.2025.100155","DOIUrl":"10.1016/j.nbas.2025.100155","url":null,"abstract":"<div><div>Subjective Cognitive Decline (SCD) is the perception of a persistent decline in cognitive function and self-reported concerns over cognitive ability in older adults with normal objective cognitive performance. SCD is associated with increased Alzheimer’s Disease (AD) risk and early AD pathology. The neurobiological underpinnings of SCD and cognitive or neural circuit alterations during SCD remain unclear. This study aimed to identify patterns of brain network functional connectivity that are associated with quantitative measures of cognitive concerns, and to examine how these functional patterns are related to performance in the cognitive domains of visual-spatial processing, attentional control, and working memory. This analysis combined data from three studies of cognitively healthy older adults which included a quantified assessment of cognitive concern severity, resting-state fMRI, and cognitive testing in the above domains. We examined brain network-to-network functional connectivity associated with self-rated cognitive concern severity, and then how the identified patterns relate to cognitive performance. Results showed that greater cognitive concern severity was associated with unique patterns of functional connectivity between the Default Mode Network and the Language and Salience Networks in older adults without objective cognitive impairment. While greater cognitive concern severity alone was associated with slower processing reaction time, these functional connectivity patterns were associated with faster processing reaction time. This suggests that these functional connectivity patterns may alter the relationship between cognitive concern severity and psychomotor slowing. These findings support that despite the perception of cognitive changes in older adults, normal cognitive performance may be maintained through functional connectivity changes in brain networks important to directing visual-spatial attention and processing.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"9 ","pages":"Article 100155"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749825","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":"Coagulation factor XII deficiency alleviates vascular dysfunction and cognitive impairment in a mouse model of cerebral β-amyloidosis and cerebral amyloid angiopathy","authors":"Marie Rouault,&nbsp;Diana Rita Kindler,&nbsp;Ruiqing Ni,&nbsp;Luca Liberale,&nbsp;Raoul Seiler,&nbsp;Giovanna D. Ielacqua,&nbsp;Roger Nitsch,&nbsp;Christopher Pryce,&nbsp;Giovanni G. Camici,&nbsp;Luka Kulic,&nbsp;Jan Klohs","doi":"10.1016/j.nbas.2026.100167","DOIUrl":"10.1016/j.nbas.2026.100167","url":null,"abstract":"<div><div>Amyloid-β (Aβ) can activate the factor XII (FXII)-driven contact system, which exerts several downstream effects on Alzheimer's disease (AD) pathology associated with cognitive impairment. Here, using genetically modified FXII deficient mice crossed with arcAβ mice, we show that genetic deletion of FXII ameliorates β-amyloidosis-mediated susceptibility to arterial thrombus formation, blood-brain barrier leakage, and cerebral microbleed load. Furthermore, we show that genetic deletion of FXII improves cognitive deficits, without affecting Aβ deposition. Thus, the FXII-driven contact system constitutes an important pathway contributing to vascular dysfunction and cognitive impairment in AD, independent of Aβ neuropathology, with important implications for the diagnosis and treatment of the disease.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"10 ","pages":"Article 100167"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148844648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health-related factors and their impact on blood-based biomarkers of Alzheimer's disease","authors":"Carolin Kurz,&nbsp;Marleen Taute,&nbsp;Paulina Tegethoff,&nbsp;Anna Hufnagel,&nbsp;Sophia Leonhardt,&nbsp;Selim Üstün Gürsel,&nbsp;Carolin Koriath,&nbsp;Alexander Jethwa,&nbsp;Gwendlyn Kollmorgen,&nbsp;Tobias Bittner,&nbsp;Daniel Keeser,&nbsp;Matthias Brendel,&nbsp;Jan Haeckert,&nbsp;Julia Utecht,&nbsp;Boris Papazov,&nbsp;Johannes Levin,&nbsp;Günter Höglinger,&nbsp;Boris-Stephan Rauchmann,&nbsp;Robert Perneczky","doi":"10.1016/j.nbas.2026.100166","DOIUrl":"10.1016/j.nbas.2026.100166","url":null,"abstract":"<div><h3>Background</h3><div>Health-related factors may influence blood-based biomarkers (BBBM) of Alzheimer's disease (AD). In this analysis, associations between modifiable factors and plasma biomarkers of neurodegeneration were investigated across the Alzheimer's disease spectrum and in cognitively healthy controls in a cerebrospinal fluid–confirmed (CSF) cohort.</div></div><div><h3>Methods</h3><div>Plasma biomarkers included the Aβ1–42/1–40 ratio, pTau181, GFAP, NFL and ApoE4. Multiple linear regression was used to test associations with lifestyle factors (physical activity and sleep), physiological factors (including renal and lipid metabolism markers), genetic factors (APOE ε4), age and sex. Percentage effect sizes and confidence intervals were calculated.</div></div><div><h3>Results</h3><div>The study included CSF-characterized individuals with AD (mild cognitive impairment due to AD and AD dementia) and cognitively healthy controls (<em>n</em> = 116; mean age 71.2 years). Overall, the associations were modest, with wide confidence intervals reflecting variability in the outcomes and the limited range of predictors in this relatively healthy sample. In CSF-confirmed participants, age emerged as the most consistent predictor of plasma biomarker levels, particularly NFL and pTau181. APOE ε3/ε4 genotype was additionally associated with higher pTau181 levels. Other demographic, metabolic and lifestyle-related variables showed only weak or inconsistent associations.</div></div><div><h3>Conclusion</h3><div>To implement BBBM in broader populations, a systematic evaluation of confounders is required. As aging cohorts present with mixed pathologies, strategies to address heterogeneity will be essential. The limited number of robust associations observed suggests that plasma biomarkers are influenced primarily by age and genetic background rather than by metabolic factors in this cohort. Validation in more diverse populations remains warranted.</div></div>","PeriodicalId":72131,"journal":{"name":"Aging brain","volume":"10 ","pages":"Article 100166"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148952243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}