Frontiers in Aging Neuroscience最新文献

{"title":"Altered brain dynamics in post-stroke cognitive and motor dysfunction.","authors":"Xiaoying Liu, Guihua Song, Xiaoyun Zhuang, Ying Zhang, Xiaoyang Wang, Yin Qin","doi":"10.3389/fnagi.2025.1640378","DOIUrl":"10.3389/fnagi.2025.1640378","url":null,"abstract":"<p><strong>Background: </strong>Current research is predominantly focused on the single dysfunction after stroke, but the potential changes in brain dynamics of post-stroke cognitive and motor dysfunction (PSCMD) remain unclear, which hinders a deep understanding of its rehabilitation effects. Therefore, the objective is to explore the dynamic brain network characteristics of PSCMD.</p><p><strong>Methods: </strong>The clinical features and resting-state functional magnetic resonance imaging (rs-fMRI) data were collected from 75 patients with post-stroke motor dysfunction (PSMD), 33 patients with PSCMD, and 35 healthy controls (HCs). Hidden markov model (HMM) was employed for the rs-fMRI data, aiming to identify the repetitive states of brain activity while further assessing the temporal properties and activation patterns in PSCMD. Additionally, the correlation between the HMM state characteristics and clinical scale scores was systematically evaluated.</p><p><strong>Results: </strong>Five HMM states were ultimately identified. According to the results, PSMD and PSCMD groups showed significant changes in the dynamics of spatiotemporal attributes versus HCs, including fractional occupancy (FO), Lifetime (LT), and transition probability (TP). Furthermore, PSCMD patients exhibited greater FO than PSMD (<i>p</i> = 0.006) in state 3. State 3 was mainly characterized by low activation of sensorimotor and higher-order cognitive networks, as well as the high activation of the right prefrontal-parietal network, which may reflect adaptive changes in the brain after PSCMD. Besides, the FO of HMM state 3 exhibited a negative connection with the MoCa score (<i>r</i> = -0.389, <i>p</i> = 0.025).</p><p><strong>Conclusion: </strong>An abnormal dynamic brain reorganization pattern could be observed in PSCMD patients. Neuromodulation strategies can be optimized by HMM-derived brain states in the future.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1640378"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039557","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":"Exercise as a multitarget therapy: modulating myokines, neurotrophins, and inflammation in Parkinson's disease.","authors":"Wei-Qi Li, Jia-Hua Yang, Lu-Lu Liu, Song-Tao Ding, Bin Yu, Lin Jiang, Ning Yan, Han-Deng Liu","doi":"10.3389/fnagi.2025.1580029","DOIUrl":"10.3389/fnagi.2025.1580029","url":null,"abstract":"<p><p>Parkinson's disease is a progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons, leading to significant motor and non-motor symptoms. Recent studies emphasize that exercise is a beneficial intervention, not only helping to decrease the risk of developing of Parkinson's disease but also alleviating existing symptoms. This review investigates the mechanisms by which exercise influences myokines, neurotrophic factors, growth factors, and inflammation-related factors to promote neuronal survival and plasticity in Parkinson's disease. Despite promising findings, the specific molecular pathways through which exercise exerts neuroprotective effects remain largely unexplored, and individual variability in disease progression necessitates personalized exercise interventions tailored to each patient's needs. Furthermore, for patients unable to engage in physical activity, exploring alternative therapies that mimic exercise to achieve neuroprotective effects is crucial. In conclusion, this review highlights the need for further research to elucidate the molecular mechanisms of exercise-induced neuroprotection and to establish effective individualized exercise programs, ultimately improving the management of Parkinson's disease.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1580029"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039604","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":"Hand dexterity and mobility independently predict cognition in older adults: a multi-domain regression analysis.","authors":"Thomas Rudolf Schneider, Ansgar Felbecker, Ben von Mitzlaff, Gregor Weissofner, Sarah Meier, Patrick Eggenberger, Simon Annaheim","doi":"10.3389/fnagi.2025.1624307","DOIUrl":"10.3389/fnagi.2025.1624307","url":null,"abstract":"<p><strong>Background: </strong>Motor function is a sensitive indicator of cognitive aging but the unique contributions of different motor domains are unclear when assessed together.</p><p><strong>Methods: </strong>We evaluated 98 community-dwelling older adults (median age: 74). From a neuropsychological battery, a primary Global Cognitive Composite score (GCCS) and three secondary domain scores were derived using Principal Component Analysis (PCA). Motor predictors included the Nine-Hole Peg Test (NHPT), grip strength, Apraxia Screen of TULIA (AST), SPPB sub-tests (5-chair-rises time (5CRT), 4 m-walk time (4MWT), balance), and inertial measurement unit (IMU)-based gait parameters. Stepwise regression controlling for age and sex identified robust predictors of the GCCS.</p><p><strong>Results: </strong>The final model identified several significant, independent motor predictors of the GCCS. Poorer hand dexterity (NHPT; <i>β</i> = -0.29, <i>p</i> < 0.01), slower 5CRT (<i>β</i> = -0.28, <i>p</i> < 0.01), and slower 4MWT (<i>β</i> = -0.17, <i>p</i> = 0.03) were associated with worse cognitive performance, while greater minimum toe clearance was associated with better performance (<i>β</i> = 0.19, <i>p</i> = 0.01). In contrast, grip strength, balance, usual gait speed, and measures of gait variability were not retained. The model explained 50.3% of the variance (Adjusted R²) in global cognitive performance.</p><p><strong>Conclusion: </strong>Hand dexterity (NHPT) and specific functional mobility tasks (5CRT, 4MWT) are robust, independent predictors of cognition in older adults. Grip strength, balance, usual gait speed, and gait variability offer limited additional value when assessed together. The NHPT and timed SPPB components are accessible, pragmatic tools for motor-cognitive research and screening.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1624307"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039566","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 multimodal MRI analysis of lecanemab treatment in mild cognitive impairment: a pilot study of structural, perfusion, and microstructural changes.","authors":"Toshiya Takahashi, Dinh Ha Duy Thuy, Shingo Takenaka, Sayaka Ono, Maya Fukui, Yasushi Okada, Tomohiko Asada, Kan Niimi, Kaku Kimura, Akio Ikeda, Ryosuke Takahashi, Riki Matsumoto, Hidenao Fukuyama","doi":"10.3389/fnagi.2025.1651596","DOIUrl":"10.3389/fnagi.2025.1651596","url":null,"abstract":"<p><strong>Background: </strong>Lecanemab, a monoclonal antibody targeting soluble amyloid-β protofibrils, has demonstrated efficacy in reducing amyloid burden in patients with mild cognitive impairment (MCI). However, its effects on brain structure, cerebral perfusion, gray matter microstructure and white matter microstructure remain unclear.</p><p><strong>Methods: </strong>This exploratory longitudinal study aimed to evaluate changes in brain volume, cerebral blood flow (CBF), and diffusion tensor imaging (DTI) measures over a 12-month treatment period in 8 patients with MCI receiving biweekly lecanemab infusions. MRI scans were acquired at baseline and at 6, 9, and 12 months using three-dimensional T1-weighted, pseudo-continuous arterial spin labeling (pCASL), and DTI sequences. Changes in whole-brain and regional indices were assessed using the Wilcoxon signed-rank test.</p><p><strong>Results: </strong>Compared to baseline, brain volume showed significant reductions at all follow-up points across all examined regions, including the whole brain, hippocampus, posterior cingulate cortex, and precuneus. CBF remained stable throughout the observation period in both global and regional analyses. Both fractional anisotropy (FA) and mean diffusivity (MD) showed significant deterioration at the whole-brain level. However, in the hippocampus, left precuneus and cingulum (cingulate gyrus), MD increased significantly at several timepoints, whereas FA remained relatively preserved, suggesting localized preservation of microstructural integrity. Neuropsychological test scores remained stable over time, with no significant deterioration observed across MMSE-J, MoCA-J, CDR-SB, or ADAS-J Cog scores. In parallel, cerebrospinal fluid biomarkers showed significant improvements in Aβ42, Aβ42/40 ratio, and p-tau181 at 6 and 12 months.</p><p><strong>Conclusion: </strong>These findings suggest that lecanemab may help maintain cerebral perfusion and partially preserve gray matter microstructure and white matter integrity during the early course of treatment in patients with MCI, despite concurrent volumetric and microstructural changes. Multimodal MRI may contribute to monitoring treatment response in patients with MCI receiving lecanemab.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1651596"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039684","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":"The manipulator behind \"Scissors\": γ -secretase and its modulators in Alzheimer's disease.","authors":"Gao Ning, Xing Fan, Du Juan, Zhao Wenxue, Wang Sijia, Chen Meinei, Dong Xiaolong, Qi Yiming","doi":"10.3389/fnagi.2025.1637671","DOIUrl":"10.3389/fnagi.2025.1637671","url":null,"abstract":"<p><p>The intramembrane aspartic protease, γ-secretase, is a heterotetrameric protein complex composed of four integral membrane proteins: presenilin (PSEN), nicastrin (NCT), Anterior pharynx defective-1 (APH-1), and presenilin enhancer 2 (PEN-2). These components are sequentially assembled into a functional complex. γ-secretase is ubiquitously expressed in all cells and tissues and exhibits enzymatic activity akin to \"molecular scissors\" by cleaving various type I transmembrane proteins. The primary substrates of this complex include amyloid precursor protein (APP) and Notch. The role of APP in the pathogenesis of Alzheimer's disease (AD) has been extensively investigated. Although γ-secretase inhibitors (GSIs) have been evaluated for their therapeutic potential in AD, their clinical application is limited due to significant toxic side effects. Recently, γ-secretase modulators (GSMs) have emerged as promising alternatives, offering new opportunities for the treatment of AD, especially the inherent γ-secretase modulatory proteins (GSMPs) within cells. Research on GSMPs has ushered in a new era for mitigating the side effects of AD drugs. In this review, we systematically summarize recent advancements in the study of γ-secretase in relation to AD and provide an overview of GSMs and GSMPs, thereby offering potential insights for the development of therapeutic strategies for AD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1637671"},"PeriodicalIF":4.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029296","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":"Correction: A bibliometric analysis of the immune system and cognitive impairment: trends from 1985 to 2024.","authors":"Beibei Zou, Jinxi Xiang, Muhua Zhang, Jing Huang, Chao Feng","doi":"10.3389/fnagi.2025.1675716","DOIUrl":"10.3389/fnagi.2025.1675716","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fnagi.2025.1587575.].</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1675716"},"PeriodicalIF":4.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014357","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":"Moderating role of triglycerides in the relationship between amyloid-β, hippocampal atrophy, and cognitive decline in mild cognitive impairment and early Alzheimer's disease.","authors":"Ji-Woo Seok, Kahye Kim, Soonjo Hwang, Kun Ho Lee, Jaeuk U Kim","doi":"10.3389/fnagi.2025.1592341","DOIUrl":"10.3389/fnagi.2025.1592341","url":null,"abstract":"<p><strong>Introduction: </strong>The role of triglycerides in Alzheimer's disease dementia (ADD) progression remains unclear. This study aimed to investigate how triglyceride levels influence the relationship between amyloid-beta (Aβ) deposition, hippocampal atrophy, and cognitive decline in individuals with mild cognitive impairment (MCI) and early-stage ADD.</p><p><strong>Methods: </strong>A total 188 older adults (170 with MCI, 18 with early ADD) from the Gwangju Alzheimer's Disease and Related cohort underwent amyloid PET and structural magnetic resonance imaging. Cognitive decline was assessed using the Korean version of the Mini-Mental State Examination (K-MMSE). A moderated mediation model (PROCESS model 7 with 10,000 bootstrap samples) was applied to examine whether hippocampal atrophy mediated the effect of Aβ on cognitive decline and whether this effect varied by triglyceride levels.</p><p><strong>Results: </strong>The indirect effect of Aβ deposition on cognitive decline through hippocampal atrophy was significant (bootstrap 95% CI: -0.39 to -0.08), while the direct effect was not. This suggests that hippocampal atrophy plays a substantial mediating role in the pathway from Aβ burden to cognitive decline, although the indirect path accounted for approximately 49% of the total effect, indicating the possibility of other unexplored mechanisms. Furthermore, moderated mediation analysis revealed that triglyceride levels significantly moderated the effect of Aβ deposition on hippocampal volume (<i>p</i> < 0.05), with higher triglyceride levels amplifying the negative impact of Aβ deposition on hippocampal atrophy.</p><p><strong>Discussion: </strong>These findings highlight hippocampal atrophy as a key pathway linking Aβ burden to cognitive impairment. Moreover, higher triglyceride levels may exacerbate Aβ-related neurodegeneration in individuals with MCI and early-stage ADD. Metabolic risk factors, such as triglycerides, may play an important role in strategies to prevent or delay cognitive decline in older adults with MCI and early ADD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1592341"},"PeriodicalIF":4.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014360","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":"Tooth loss impairs cognitive function in SAMP8 mice by aggravating pyroptosis of microglia via the cGAS/STING pathway.","authors":"Xu Sun, Yunping Lu, Jiangqi Hu, Shixiang Meng, Xiaoyu Wang, Qingsong Jiang","doi":"10.3389/fnagi.2025.1628520","DOIUrl":"10.3389/fnagi.2025.1628520","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's Disease (AD) is a common neurodegenerative disease among the elderly population. It has been posited that the onset and progression of AD are influenced by a combination of various factors. Occlusal support loss due to tooth loss has been reported to be a risk factor triggering cognitive dysfunction. This study aimed to investigate the relationship between tooth loss and cognitive dysfunction and illustrate the role of pyroptosis in advancing Alzheimer's disease.</p><p><strong>Methods: </strong>Male 5-month-old senescence-accelerated mouse strain P8 (SAMP8) mice were divided into two groups (n = 6): the S (sham-operated) and TL (tooth loss) groups. We assessed spatial memory ability using the Y-maze and Novel Object Recognition (NOR) tests. In addition, we performed pathological and molecular biological assessments of the hippocampus to evaluate pyroptosis-related indicators and changes in cGAS/STING. We further verified the correlation between the two <i>in vitro</i>.</p><p><strong>Results: </strong>The pathological section staining revealed an upregulation of GSDMD, a target protein of pyroptosis, and abnormal activation of the cGAS/STING pathway, particularly in microglia, after tooth loss. <i>In vitro</i>, we demonstrated that the BV2 microglia knockdown STING group improved the inflammatory cascade response and down-regulated the pyroptotic features.</p><p><strong>Discussion: </strong>These data suggest that the occlusal support loss due to tooth loss induces pyroptosis-related protein deposition, which may be intimately associated with the cGAS/STING signaling pathway. This provides new insights into the treatment and prevention of oral health and cognitive behavioural disorders in the elderly population.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1628520"},"PeriodicalIF":4.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014346","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":"Disrupted calcium dynamics and electrophysiological activity in the stratum pyramidale and hippocampal alveus during fear conditioning in the 5xFAD model of Alzheimer's disease.","authors":"Alexander Erofeev, Egor Vinokurov, Anastasia Bol'shakova, Ilya Bezprozvanny, Olga Vlasova","doi":"10.3389/fnagi.2025.1550673","DOIUrl":"10.3389/fnagi.2025.1550673","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive decline and significant disruptions in hippocampal neural networks, critically impacting memory and learning. Understanding the neural mechanisms underlying these impairments is essential for developing effective therapies. The 5xFAD mouse model, known for progressive neurodegeneration and cognitive deficits, provides a valuable platform for investigating associative learning and memory impairments related to AD. However, the <i>in vivo</i> electrophysiological state of the hippocampal alveus in 5xFAD mice during learning and memory formation remains poorly understood. Here, we performed <i>in vivo</i> one-photon calcium imaging of CA1 hippocampal neurons with wireless electrophysiological recordings from the hippocampal alveus in freely moving 5xFAD mice to explore specific neural alterations during a fear conditioning test. Our results demonstrate significant deficits in the learning and memory capacities of 5xFAD mice, showing impairments in hippocampal-dependent contextual and tone-associated memory retrieval, along with disrupted calcium dynamics and impaired electrophysiological activity in the hippocampal alveus. These findings reveal patterns of network dysregulation associated with AD. These findings enhance our understanding of the specific neural dysfunctions contributing to the cognitive decline associated with memory loss in AD and emphasize the value of applying <i>in vivo</i> methods to elucidate neurodegenerative mechanisms. This approach provides a foundation for future studies on AD pathophysiology and may inform the development of targeted therapeutic strategies to mitigate memory impairments in AD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1550673"},"PeriodicalIF":4.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000140","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":"Virtual reality navigation for the early detection of Alzheimer's disease.","authors":"Sayuri Shima, Reiko Ohdake, Yasuaki Mizutani, Harutsugu Tatebe, Riki Koike, Atsushi Kasai, Epifanio Bagarinao, Kazuya Kawabata, Akihiro Ueda, Mizuki Ito, Junichi Hata, Shinsuke Ishigaki, Junichiro Yoshimoto, Hiroshi Toyama, Takahiko Tokuda, Akihiko Takashima, Hirohisa Watanabe","doi":"10.3389/fnagi.2025.1571429","DOIUrl":"10.3389/fnagi.2025.1571429","url":null,"abstract":"<p><strong>Objective: </strong>The development of non-invasive clinical diagnostics is paramount for the early detection of Alzheimer's disease (AD). Neurofibrillary tangles in AD originate from the entorhinal cortex, a cortical memory area that mediates navigation via path integration (PI). Here, we studied correlations between PI errors and levels of a range of AD biomarkers using a 3D virtual reality navigation system to explore PI as a non-invasive surrogate marker for early detection.</p><p><strong>Methods: </strong>We examined 111 healthy adults for PI using a head-mounted 3D VR system, AD-related plasma biomarkers (GFAP, NfL, Aβ40, Aβ42, and p-tau181), Apolipoprotein E (ApoE) genotype, and demographic and cognitive assessments. Covariance of PI and AD biomarkers was assessed statistically, including tests for multivariate linear regression, logistic regression, and predictor importance ranking using machine learning, to identify predictive relationships for PI errors.</p><p><strong>Results: </strong>We found significant positive correlations between PI errors with age and plasma GFAP, p-tau181, and NfL levels. Multivariate analysis identified significant correlations of plasma GFAP (<i>t</i>-value = 2.16, <i>p</i> = 0.0332) and p-tau181 (<i>t</i>-value = 2.53, <i>p</i> = 0.0128) with PI errors. Predictor importance ranking using machine learning and receiver operating characteristic curves identified plasma p-tau181 as the most significant predictor of PI. ApoE genotype and plasma p-tau181 showed positive and negative PI associations (ApoE: coefficient = 0.650, <i>p</i> = 0.037; p-tau181: coefficient = -0.899, <i>p</i> = 0.041). EC thickness exhibited negative correlations with age, mean PI errors, and GFAP, NfL, and p-tau181; however, none of these associations remained significant after adjusting for age in linear regression analyses.</p><p><strong>Conclusion: </strong>These findings suggest that PI quantified by 3D VR navigation systems may be useful as a surrogate diagnostic tool for the detection of early AD pathophysiology. The hierarchical application of 3D VR PI and plasma p-tau181, in particular, may be an effective combinatorial biomarker for early AD neurodegeneration. These findings advance the application of non-invasive diagnostic tools for early testing and monitoring of AD, paving the way for timely therapeutic interventions and improved epidemiological patient outcomes.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1571429"},"PeriodicalIF":4.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000093","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}