Journal of Alzheimer's Disease最新文献

{"title":"The ferroptosis-lipid metabolism-neuroinflammation axis in Alzheimer's disease: A review of mechanistic interplay and therapeutic implications.","authors":"Tao Zhu, Xu Deng, Jia Lu, Xing Zhou, Yu Wang, Dandan Xu, Jian Song, Xixiang Xie, Chunxia Chen","doi":"10.1177/13872877261495962","DOIUrl":"https://doi.org/10.1177/13872877261495962","url":null,"abstract":"<p><p>Alzheimer's disease (AD) involves multiple pathological pathways, with ferroptosis and lipid metabolic dysregulation forming a coupled mechanism across the disease course, and neuroinflammation acting as a key mediator. While existing reviews often focus on isolated processes, they frequently lack an integrative analysis of the \"ferroptosis-lipid-neuroinflammation axis\" as a systemic pathological core. This review specifically addresses this gap by proposing a unified mechanistic framework for neuronal injury, synaptic dysfunction, and immunometabolic remodeling in AD, centered on this tripartite axis. We comprehensively summarize how key pathways involving glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), coenzyme Q10 (CoQ10), the cystine/glutamate antiporter system Xc^-, solute carrier family 7 member 11 (SLC7A11), AMP-activated protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), and N6-methyladenosine (m⁶A) regulation shape neuroinflammation within this context. Furthermore, we explore how advanced methodologies, including spatial omics, single-cell transcriptomics, organoid models, and engineered exosome methods, are instrumental in elucidating regional specificity, optimal intervention windows, and targeted delivery strategies for modulating this iron-lipid-inflammation interplay. This axis functions as a pathological amplifier, linking metabolic, oxidative, immune, and structural dysfunctions. Its systemic reprogramming offers a new paradigm for AD subtyping, biomarker discovery, and multitarget interventions, thereby overcoming the limitations of traditional amyloid-β/tau-centric approaches. This review integrates literature published up to the submission date, ensuring the inclusion of the latest mechanistic insights and translational advances in the ferroptosis-lipid metabolism-neuroinflammation axis.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261495962"},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181951","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":"Intermittent hypoxia training alleviates cerebral hypoperfusion and amyloid-β deposition in a mixed dementia model established by bilateral common carotid artery stenosis in early-stage 5xFAD mice.","authors":"Chenchen Lv, Qi Luo, Feiyang Jin, Qianqian Shao, Yunjie Qiu, Junjun Ni, Jia Liu, Hong Qing, Zhenzhen Quan","doi":"10.1177/13872877261497235","DOIUrl":"https://doi.org/10.1177/13872877261497235","url":null,"abstract":"<p><p>BackgroundAlzheimer's disease (AD) is the most common form of dementia and often coexists with vascular pathology in clinical settings, resulting in mixed dementia with more severe symptoms and more rapid progression.ObjectiveTo investigate whether chronic cerebral hypoperfusion aggravates early AD-related pathology, we established a mixed dementia-like model by inducing bilateral common carotid artery stenosis (BCAS) in early-stage 5xFAD mice and evaluated the effects of intermittent hypoxia treatment (IHT).MethodsEarly-stage 5xFAD mice were subjected to BCAS to induce chronic cerebral hypoperfusion. Cognitive performance, cerebral perfusion, amyloid-β (Aβ) deposition, glial reactivity, tight-junction transcripts, and perivascular astrocyte-vascular organization were assessed. The therapeutic effects of IHT were then evaluated in this mixed dementia-like model.ResultsBCAS-induced hypoperfusion aggravated cognitive impairment in early-stage 5xFAD mice and accelerated pathological changes, including increased Aβ burden and stronger glial reactivity. These changes were accompanied by altered tight-junction transcripts and impaired perivascular astrocyte-vascular organization. IHT mitigated several features of the mixed dementia phenotype, including cerebral hypoperfusion, Aβ accumulation, glial reactivity, and altered perivascular AQP4/CD31 organization, while partially improving cognitive performance.ConclusionsChronic cerebral hypoperfusion can exacerbate early AD-related pathological and cognitive changes. IHT may alleviate mixed dementia-like phenotypes by improving cerebral perfusion, with accompanying changes in perivascular AQP4/CD31 organization and tight-junction transcripts.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261497235"},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181919","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":"Emerging hydrogel platforms for disease modeling, diagnosis, and imaging of Alzheimer's disease.","authors":"Travis D Truong, Huachen Shi, Claudia Pena, Baskaran Chinnappan, Esha Savani, Amanpreet Cheema, Naushira Pandya, Nancy G Klimas, Theoharis C Theoharides, Duraisamy Kempuraj","doi":"10.1177/13872877261495937","DOIUrl":"https://doi.org/10.1177/13872877261495937","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of amyloid plaques, neurofibrillary tangles, neurodegeneration, cognitive decline, and dementia. The exact pathogenesis is not well understood, as appropriate pathological and therapeutically relevant disease models remain limited. Hydrogels are hydrophilic, three-dimensional (3D) polymer networks composed of synthetic or natural materials and have diverse neuroscience applications, including drug delivery, tissue engineering, and regenerative medicine. Currently, hydrogel in vitro platforms are becoming increasingly explored for AD pathogenesis, as brain extracellular matrix-mimicking biodegradable components, for delivery of growth factors for neurons and other brain cells, AD-specific peptide release, engineered multi-region brain organoids, and therapeutic drug delivery. Beyond disease modeling, hydrogels are being used to evaluate emerging AD diagnostic and therapeutic strategies, such as biomarker sensing and the integration of imaging. Recent AD diagnostic platforms have leveraged hydrogels as biomolecule-capture matrices and signal-transduction elements to detect AD-associated biomarkers via minimally invasive or implantable systems. Hydrogels have also been harnessed in magnetic resonance imaging, ultrasound, computed tomography, and positron emission tomography imaging modalities to support imageable vehicles for therapeutic delivery. Such platforms hold promise for bridging physiologically relevant neurobiological investigation with more accessible, efficient clinical tools for AD. This review highlights recent advances in hydrogel-based disease models, diagnostic tools, and imaging technologies and their potential to integrate with brain organoids, artificial intelligence, and 3D printing to enhance mechanistic and translational applications for AD.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261495937"},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181953","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":"Effects of aerobic exercise on learning and memory function and inflammatory markers in animal models of Alzheimer's disease: A meta-analysis.","authors":"Rumeng Liu, Jiping Chen, Shuan Xue, Yanfeng Dong, Xiangli Xue","doi":"10.1177/13872877261496469","DOIUrl":"https://doi.org/10.1177/13872877261496469","url":null,"abstract":"<p><p>BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Aerobic exercise (AE) may improve learning and memory function and modulate neuroinflammation in AD animal models, although evidence remains inconsistent.ObjectiveTo evaluate the effects of AE on learning and memory function and hippocampal inflammatory cytokines in AD animal models.MethodsThis systematic review and meta-analysis followed the PRISMA statement. We searched PubMed, Scopus, Embase, Web of Science, and the Cochrane Library, and included 19 animal studies. We used random-effects models to calculate standardized mean differences (SMD). We conducted subgroup analyses by AD modeling methods, exercise modality, AD pathological stage, and intervention duration. We also evaluated oxidative stress-related markers reported in the included studies as supplementary outcomes.ResultsAE significantly improved spatial memory (platform crossings, SMD = 1.82), spatial learning (escape latency, SMD = -1.48), and recognition memory (novel object recognition, SMD = 2.80). AE reduced hippocampal interleukin-1β (IL-1β) levels (SMD = -3.17); AE showed a trend toward reducing tumor necrosis factor-α (TNF-α) levels, but the effect did not reach statistical significance (SMD = -1.20, 95% CI: -2.44 to 0.04). Supplementary analyses showed that AE increased superoxide dismutase (SOD) activity (SMD = 2.05) and reduced malondialdehyde (MDA) content (SMD = -3.20). Moderate-to-high heterogeneity was observed across studies.ConclusionsAE improves learning and memory function and modulates hippocampal inflammation in AD animal models, particularly IL-1β. Supplementary analyses suggest potential benefits for oxidative stress, with increased SOD and reduced MDA.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261496469"},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181938","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":"Education as a proxy for cognitive reserve, and its moderating role in the amyloid-cognition relationship across the Alzheimer's disease continuum: A systematic review and meta-analysis.","authors":"Yuan Yang, Yun Zhang, Jaymie R Meliker, Lauren L Richmond, Dylan M Smith, Sean A P Clouston","doi":"10.1177/13872877261496419","DOIUrl":"https://doi.org/10.1177/13872877261496419","url":null,"abstract":"<p><p>BackgroundEducational achievement is widely used as a proxy for cognitive reserve-the capacity to sustain cognition despite accumulating neuropathology. Nevertheless, the impact of education on the neuropathology-cognition association has not been assessed in a meta-analytical manner.ObjectiveTo meta-analyze studies reporting an education × neuropathology interaction term on cognition by pathology, and to determine whether the interaction effect differs by cognitive domains, age, participants' cognitive diagnosis, and gender.MethodsFollowing PRISMA guidelines, we searched PubMed, EMBASE, PsycINFO, and Web of Science through March 2026. Seventeen cross-sectional articles contributing 82 effect sizes were pooled using random-effects models with robust variance estimation across four pathology classes (amyloid, phosphorylated tau [pTau], vascular, and structural). All analyses were corrected for multiple comparisons using the Benjamini-Hochberg false-discovery rate (FDR).ResultsHigher education significantly attenuated the amyloid-cognition association (r = 0.114, adjusted-p = 0.012), a trend concentrated in the global cognitive domain (r = 0.108, adjusted-p = 0.060) and in studies with mixed cognitively unimpaired and cognitively impaired participants (r = 0.130, adjusted-p = 0.020). No significant interaction was found for pTau, vascular, or structural pathology (all adjusted-p > 0.100). Funnel plot and Egger's regression showed no evidence of publication bias.ConclusionsEducation moderated the amyloid-cognition association across the Alzheimer's disease continuum in full-spectrum (mixed-diagnosis) samples. Confirmation in adequately powered, longitudinal designs is warranted.PROSPERO Registration: CRD42023390544.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261496419"},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181959","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":"A scoping review on the time to diagnosis, early symptoms, and the barriers and facilitators of diagnosis in young-onset dementia.","authors":"Charles David, Stevie Hendriks, Line Damsgaard, Sebastian Köhler, Marjolein de Vugt","doi":"10.1177/13872877261495145","DOIUrl":"https://doi.org/10.1177/13872877261495145","url":null,"abstract":"<p><p>BackgroundYoung-onset dementia (YOD) occurs when symptoms start before age 65 and affects about 3.9 million people globally. Variability in first symptoms, the young age, and prevalent non-cognitive symptoms pose challenges in recognizing YOD, leading to diagnostic delays. Better awareness and recognition of warning signs in primary care is essential for early YOD diagnosis, facilitating access to appropriate services and informal care arrangements.ObjectiveTo gain insights into the prediagnostic phase of YOD by exploring literature on early symptoms and factors influencing a timely diagnosis.MethodsA literature search was conducted across PubMed, Embase, Web of Science, and PsycInfo. Two independent reviewers screened 5862 titles and abstracts and assessed 790 full texts. Data extraction used a standardized form, including time to diagnosis, early symptoms, barriers, and facilitators to YOD diagnosis. Review reporting followed PRISMA-ScR guidelines. Focus group discussions with people with YOD, caregivers, and healthcare professionals (HCPs) contextualized the review findings.ResultsWe included 225 studies. Time to diagnosis ranged from 4 months to 15 years across dementia subtypes. Early symptoms included memory problems, language difficulties, disorientation, personality changes, delusions, hallucinations, apathy, and depression. HCPs, people with YOD, and their caregivers often lacked awareness of YOD, which hindered diagnosis. However, persistence in seeking medical care, YOD-related services, and couples' agreements to seek professional help were essential facilitators.ConclusionsEarly signs of YOD include cognitive, behavioral, and affective symptoms. Lack of YOD awareness hinders diagnosis, highlighting the need to raise awareness among HCPs and the community to promote early identification.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261495145"},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181896","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":"Psychological impact of the use of blood-based biomarkers for mild cognitive impairment in primary care.","authors":"Takuya Ataka, Noriyuki Kimura, Temmei Ito, Naoki Kaneko, Teruaki Masuda, Tsukasa Takeuchi, Takehiko Miyagawa, Shinichi Iwamoto, Etsuro Matsubara","doi":"10.1177/13872877261494606","DOIUrl":"https://doi.org/10.1177/13872877261494606","url":null,"abstract":"<p><p>BackgroundBlood-based biomarker testing in primary care could contribute to the early diagnosis of Alzheimer's disease. The usefulness of using blood-based biomarker in the primary care has evaluated, but their psychological impact has not been examined.ObjectiveThe primary objective of this study is to investigate the psychological impact of disclosing results to patients and evaluate the changes in confidence of diagnoses by physicians. As a secondary objective, we compare the psychological impact with positron emission tomography.MethodsThis study included adults aged ≥50 years with suspected mild cognitive impairment or mild dementia. In total, 97 were analyzed in this study. All participants underwent blood-based biomarker testing and the results were disclosed by primary care physicians or specialists. Psychological impact was measured using the Impact of Event Scale-Revised 1 week after disclosure. Physician diagnostic confidence, changes in diagnosis and management actions were also recorded.ResultsNineteen participants had negative blood-based biomarker results but positive PET results. The Impact of Event Scale-Revised scores were low after blood-based biomarker disclosure and did not differ by health care provider. Blood-based biomarker results prompted changes in diagnosis in 41.9% of cases. The diagnostic confidence increased after disclosure of the blood-based biomarker. Physicians reported a moderate/strong impact on management in 81.5% of cases after the disclosure of blood-based biomarkers.ConclusionsIn this study, blood-based biomarker result disclosure to patients with mild cognitive impairment had minimal short-term psychological burden and informed clinical decisions. These findings support the integration of blood-based biomarker testing into dementia care.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261494606"},"PeriodicalIF":3.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164891","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":"Prevalence and impact of cerebral small vessel lesions in mild cognitive impairment and mild dementia due to Alzheimer's disease patients in memory clinic: Preparation for anti-amyloid therapy in Thailand.","authors":"Thachamai Smitasiri, Thanakit Pongpitakmetha, Sekh Thanprasertsuk, Yuttachai Likitjaroen","doi":"10.1177/13872877261493065","DOIUrl":"https://doi.org/10.1177/13872877261493065","url":null,"abstract":"<p><p>BackgroundAlzheimer's disease (AD) raises global concern with its impact on daily living. Anti-amyloid therapy (AAT) are specific treatments used in mild cognitive impairment (MCI) and mild dementia stage of AD (mild AD). Severe cerebral small vessel disease (SVD) lesions such as microbleeds, superficial siderosis, lacunes, white matter hyperintensities are listed as exclusions criteria for AAT. In Thailand, there is no prevalence study of SVD lesions specifically in these patient groups.ObjectiveThe purpose of this study is to report the prevalence of SVD burdens which are excluded in AAT, in MCI and mild AD patients in Thailand.MethodsThe study was carried out at Memory Clinic in King Chulalongkorn Memorial Hospital. Patients with amnestic MCI and mild AD were diagnosed using clinical criteria, cognitive tests and brain MRI. Visual rating scales were used to evaluate SVD burden based on STRIVE-2 criteria. Baseline characteristics and cognitive tests were retrieved from electronic medical records.ResultsThe study involving 102 patients, 73.5% had MCI, and 26.5% had mild AD. Twenty-one individuals (20.6%) had either more than 4 microbleeds, more than 2 lacunes, or Fazekas score of 3. There was no evidence of superficial siderosis. Individuals without microbleeds had a higher TMSE score (25.4 versus 23.5; p = 0.009).ConclusionsAmong patients with MCI and mild AD, 20.6% met the exclusion criteria for AAT, in part of SVD lesions. These findings provide important information for evaluating the cost-effectiveness of AAT, which become a treatment option for Thai AD patients.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261493065"},"PeriodicalIF":3.4,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166072","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":"Noise or clearance? Reframing plasma amyloid-β variability in Alzheimer's disease as a measurable clearance signal.","authors":"Soufiane Ben Brik","doi":"10.1177/13872877261496533","DOIUrl":"https://doi.org/10.1177/13872877261496533","url":null,"abstract":"<p><p>Plasma biomarkers, and the amyloid-β 42/40 ratio in particular, are increasingly used to stage Alzheimer's disease and to stratify and monitor clinical trials, on the tacit assumption that a single measurement reflects a stable, steady-state level of pathology. A recent micro-longitudinal study that sampled plasma weekly for five weeks in people with Alzheimer's disease challenged that assumption, reporting that most participants varied by more than half in the amyloid-β 42/40 ratio over that short window. The reflexive response is to treat such movement as measurement noise to be averaged away. Here I argue that a meaningful part of it is unlikely to be noise. In healthy adults the same ratio is among the most stable plasma analytes, so instability concentrated in disease is difficult to attribute to the assay alone. Brain-to-blood clearance of amyloid-β is itself dynamic over days, rising with sleep and falling with fragmentation, apnoea, poor cerebral perfusion, autonomic dysregulation, and sedating or anticholinergic drugs. An instantaneous plasma value therefore partly reports the clearance state of the preceding night. This clearance account is kept distinct from analytical and pre-analytical variance, and from oligomeric amyloid-β dynamics, which are considered separately. The practical problem is not the variance itself but that we measure the molecule without measuring the physiological state that moves it. I propose that an inexpensive, repeatable, bedside index of that state, illustrated here with the Systemic BenBrik Geriatric Score, could be recorded alongside each plasma draw and modelled as a covariate, converting nuisance variance into interpretable signal. The prediction is falsifiable, and a validation design is outlined. This is a hypothesis, not a validated result; the illustrative index used here, the Systemic BenBrik Geriatric Score, is not a validated measure.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261496533"},"PeriodicalIF":3.4,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164637","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":"Interaction of physical fitness and resting state functional connectivity on global cognitive function in older adults with mild cognitive impairment.","authors":"Yi Gu, Teresa Liu-Ambrose, Ryan S Falck, Lindsay S Nagamatsu, Roger C Tam, Ging-Yuek Robin Hsiung, Lisanne Ten Brinke, Alexis Bullock, Sofia Grant, Chun Liang Hsu","doi":"10.1177/13872877261491995","DOIUrl":"https://doi.org/10.1177/13872877261491995","url":null,"abstract":"<p><p>BackgroundMild cognitive impairment (MCI) represents a prodromal stage of Alzheimer's disease. Physical fitness, including cardiorespiratory fitness and muscular strength, is associated with cognitive function in older adults. Resting-state functional connectivity (rsFC) is also linked to cognitive function; however, whether physical fitness modifies the association between rsFC and cognitive function remains unclear.ObjectiveTo examine associations of cardiorespiratory fitness and muscular strength with rsFC and their interaction on global cognitive function in older adults with MCI.MethodsA cross-sectional study of 95 older adults with MCI. Cardiorespiratory fitness was estimated by the 400-m walk; muscular strength was indexed using grip strength measured by hand dynamometer. Global cognitive function was indexed by the 13-item Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog-13). Using the Yeo 7-network atlas, we computed rsFC within and between seven canonical networks. Significant rsFC-fitness associations were entered into moderation analyses (X = rsFC, Y = ADAS-Cog-13) with cardiorespiratory fitness or grip strength as moderator, adjusted for covariates. Simple slopes were examined at ±1 SD from the mean of moderator.ResultsParticipants had a mean age of 73.49 years, and 53.7% were female. Cardiorespiratory fitness interacted with rsFC in relation to ADAS-Cog-13, whereas grip strength did not. Specifically, greater limbic-visual (standardized <i>b</i> = -0.22, <i>p</i> = 0.009), limbic-somatomotor (<i>b</i> = -0.20, <i>p</i> = 0.049), and limbic-ventral attention (<i>b</i> = -0.19, <i>p</i> = 0.020) rsFC were associated with better global cognitive function among individuals with higher cardiorespiratory fitness.ConclusionsHigher between-network rsFC is generally associated with worse cognitive function. Thus, higher cardiorespiratory fitness may attenuate the negative association between higher between-network rsFC and global cognitive function in MCI.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877261491995"},"PeriodicalIF":3.4,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164337","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}