Alzheimer's Research & Therapy最新文献

{"title":"Glycolysis-enhancing α₁-adrenergic antagonists have therapeutic potential in Alzheimer's disease.","authors":"Qiang Zhang, Jordan L Schultz, Jacob E Simmering, Braedon Q Kirkpatrick, Matthew A Weber, Sydney Skuodas, Tara Hicks, Grace Pierce, Margaret Laughlin, Benu George, Aimee X Bertolli, Travis Larson, Ramasamy Thangavel, Mayu Oya, David K Meyerholz, Georgina Aldridge, Jan Fassler, Nandakumar S Narayanan","doi":"10.1186/s13195-026-02135-z","DOIUrl":"10.1186/s13195-026-02135-z","url":null,"abstract":"<p><strong>Background: </strong>Terazosin (TZ) is widely prescribed for hypertension and benign prostatic hyperplasia. Recent studies suggest that TZ enhances glycolysis and may protect against neurodegenerative diseases.</p><p><strong>Methods: </strong>We tested the hypothesis that TZ is neuroprotective in Alzheimer's disease (AD) in a yeast model, a mouse model, and two human datasets.</p><p><strong>Results: </strong>We report four main results. First, TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired metabolism, and reduced Amyloid-beta42 (Aβ42) aggregation. Second, in 5xFAD mice, TZ attenuated amyloid pathology and rescued cognitive impairments in spatial memory and interval timing. Third, in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, AD patients taking glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and metabolic neuroimaging biomarkers (18 F-fluorodeoxyglucose positron emission tomography (FDG-PET)). Finally, in the Merative Marketscan dataset, patients taking glycolysis-enhancing drugs had lower risks of developing AD.</p><p><strong>Conclusion: </strong>These data provide preliminary evidence that glycolysis-enhancing drugs have therapeutic potential in AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical outcomes after antipsychotic discontinuation in nursing home residents with dementia: a nationwide cohort study.","authors":"Chun-Ting Yang, James M Wilkins, Aaron S Kesselheim, Dae Hyun Kim, Kueiyu Joshua Lin","doi":"10.1186/s13195-026-02134-0","DOIUrl":"10.1186/s13195-026-02134-0","url":null,"abstract":"<p><strong>Background: </strong>Antipsychotic medications in people with dementia should be avoided or limited to treatment courses of fewer than 3-4 months. It is unknown whether discontinuation of long-term antipsychotic medications in this population can improve clinical outcomes. This study evaluated clinical outcomes associated with discontinuation of long-term antipsychotic medication use compared with continued use among individuals with dementia residing in nursing homes.</p><p><strong>Methods: </strong>This cohort study used Medicare claims data (2013-2022) linked to Minimum Data Set clinical assessment data. The study population included nursing home residents aged ≥ 65 with dementia who had used antipsychotic medications for more than 90 days. Individuals who discontinued antipsychotic medications (gap ≥ 60 days) were matched to continuers using incidence density sampling based on time since first prescription of antipsychotic medications. Propensity score matching was applied to adjust for 86 covariates. Study outcomes included all-cause hospitalization, specific rehospitalization reasons, and all-cause mortality. Hazard ratios (HRs) were estimated using Cox proportional hazards model, and rate differences (RDs) per 1,000 person-years were estimated using generalized linear models.</p><p><strong>Results: </strong>Two thousand one hundred eleven propensity score-matched pairs were included and followed for a median of 298 days. Antipsychotic medication discontinuation versus continuation was associated with lower risk of all-cause hospitalization (HR [95% CI]: 0.83 [0.72, 0.96]; RD [95% CI]: -55.85 [-97.82, -13.88]) and hospitalization for pneumonia (HR: 0.51 [0.29, 0.90]; RD: -12.85 [-23.26, -2.44]) or urinary tract infections (HR: 0.47 [0.26, 0.83]; RD: -14.22 [-24.62, -3.83]); non-significantly lower risks of hospitalization for falls (HR: 0.88 [0.70, 1.11]; RD: -13.19 [-37.78, 11.41]), delirium (HR: 0.76 [0.57, 1.02]; RD: -19.26 [-39.18, 0.66]), stroke (HR: 0.95 [0.42, 2.16]; RD: -0.31 [-7.06, 6.44]), and all-cause mortality (HR: 0.89 [0.79, 1.02]; RD: -38.23 [-81.01, 4.54]). Subgroup analyses showed the greatest reduction in hospitalization risk was among individuals with moderate-to-severe dementia (HR: 0.78 [95% CI: 0.65, 0.93]; RD: -96.76 [-163.75, -29.77]).</p><p><strong>Conclusions: </strong>Among nursing home residents with dementia, discontinuing long-term antipsychotic medication use was associated with lower risks of hospitalization, pneumonia, and urinary tract infections, suggesting clinical benefits in this population.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic pain as a risk factor for Alzheimer's disease pathology: a longitudinal ADNI study.","authors":"Tyler R Bell, Carol E Franz, Christine Fennema-Notestine, Erin E Sundermann, Shelby B Hughes, Matthew S Panizzon, Imanuel Lerman, Jeremy A Elman, William S Kremen","doi":"10.1186/s13195-026-02137-x","DOIUrl":"10.1186/s13195-026-02137-x","url":null,"abstract":"<p><strong>Background: </strong>Growing evidence supports chronic pain (CP) as a risk factor for Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). We examined whether CP is associated with longitudinal worsening of AD-related biomarkers, brain structure, and cognition, and whether effects differ by APOE-ε4 status.</p><p><strong>Methods: </strong>Data were drawn from 1,493 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) without baseline dementia (mean age = 72.4 ± 7.19 years; 48% female). Linear mixed-effects models tested longitudinal change in cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid-β (Aβ) and phosphorylated tau (p-tau181), structural MRI indices (AD-related cortical signature, hippocampal and entorhinal volumes, precuneus thickness), and cognitive outcomes (episodic memory, executive function, Mini-Mental State Examination [MMSE]). Models included fixed effects of CP status, APOE-ε4 status, time (years since baseline), and their two-way and three-way interactions, adjusting for age, sex, education, baseline Aβ positivity status, and time-varying depressive symptoms.</p><p><strong>Results: </strong>At baseline, 30% of participants (n = 452) reported CP and 45% (n = 666) were APOE-ε4 carriers. CP and APOE-ε4 status did not independently predict baseline CSF Aβ42/Aβ40, PET Aβ burden, or CSF p-tau181. Longitudinally, the CP+/ε4 + group showed greater AD-like changes in CSF Aβ42/Aβ40 and CSF p-tau181, thinning of the precuneus (β=-0.09, p<.001) and faster decline in episodic memory (β=-0.08, p<.001), compared to all other groups. Many of these associations remained when excluding participants with MCI or restricting to Aβ-negative participants.</p><p><strong>Conclusions: </strong>The combination of CP and APOE-ε4 carriership was associated with greater longitudinal worsening of brain structure and cognitive function, even among individuals who were Aβ-negative at baseline. These findings provide in vivo evidence that CP is associated with greater AD-related worsening over time in the context of genetic susceptibility. As evidence accumulates, CP may warrant recognition as a risk factor in dementia prevention frameworks, though causal inferences require further study.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"γ-radiation reduces phosphorylated-tau in rhesus macaque brains: potential implications for Alzheimer's disease and other tauopathies.","authors":"Erin K Murphy, Kathleen Hatch, Stephen Y Wise, Oluseyi O Fatanmi, Sarah A Petrus, Manish Bhomia, Daniela Lecca, Barbara E C Knollmann-Ritschel, Daniel P Perl, Vijay K Singh, Diego Iacono","doi":"10.1186/s13195-026-02128-y","DOIUrl":"10.1186/s13195-026-02128-y","url":null,"abstract":"<p><strong>Background: </strong>Studies on the effects of γ-radiation on nonhuman primate (NHP) brains are limited, despite the critical need to understand the impact of radiation exposure on the brain from various sources like radiotherapy equipment, space travel, and potential nuclear events.</p><p><strong>Methods: </strong>We investigated molecular and neuropathological changes in rhesus macaque brains after a single 5.8 Gy total-body γ-radiation exposure. We analyzed samples dissected from frontal cortex (FCtx), hippocampus (Hippo), and cerebellum (CRB) of irradiated (RAD) vs. unirradiated/control (CTRL) animals. Western blotting and digital PCR (dPCR) analyses were used to measure different phosphorylated-Tau (pTau) forms and neurodegeneration markers (i.e., amyloid protein precursor [APP], neurofilament-light chain [NFL], glial fibrillary acidic protein [GFAP], ionized calcium-binding adapter molecule 1 [IBA1/AIF1], and myelin basic protein [MBP]).</p><p><strong>Results: </strong>We detected lower levels of different forms of soluble pTau species (pTau181, and pTau217, among others) in RAD vs. CTRL animals across all three examined brain regions. While APP and GFAP levels were unchanged in the FCtx, increased IBA1 and NFL levels were detected alongside decreased MBP levels. Moreover, dPCR data identified decreased expression of GFAP and MBP in the FCtx. Importantly, the molecular changes observed were not accompanied by overt signs of neurodegeneration or cellular abnormalities upon neuropathological assessment.</p><p><strong>Conclusions: </strong>These findings in irradiated NHPs' brains are novel and indicate that a single total-body γ-radiation exposure significantly alters soluble pTau levels after a few weeks from irradiation without causing obvious neurohistological damage. These results open intriguing new possibilities of exploring γ-radiation-based strategies to modulate the progression of tauopathies, including Alzheimer's disease.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential of key Alzheimer's plasma biomarkers to mimic tau PET MUBADA-based disease staging.","authors":"Inge M W Verberk, Lotte A de Koning, Emma M Coomans, Calvin Trieu, Anna E Leeuwis, Jacob Hunter, Lee Honigberg, Wiesje M van der Flier, Everard G B Vijverberg, Rik Ossenkoppele, Elsmarieke van de Giessen, Charlotte E Teunissen","doi":"10.1186/s13195-026-02085-6","DOIUrl":"10.1186/s13195-026-02085-6","url":null,"abstract":"<p><strong>Background: </strong>Patients with Alzheimer's disease (AD) with a low to intermediate tau-PET burden might benefit most from anti-amyloid treatment. Staging tau burden with plasma biomarkers would offer a scalable alternative to staging with tau-PET. This study investigated whether key plasma biomarkers P-tau217, P-tau181, Aβ42/40, GFAP and NfL can be used to accurately stage amyloid status (A-/A+) and tau-PET burden, and evaluated the relation of such a plasma-based staging system with cognitive outcomes over time.</p><p><strong>Methods: </strong>We included 105 participants with subjective cognitive decline (n = 27 A-, n = 18 A+), A+ mild cognitive impairment (n = 10) or A + AD-dementia (n = 50) from the Amsterdam Dementia Cohort who underwent [¹⁸F]flortaucipir PET-burden assessment (T_low, T_intermediate or T_high; based on MUBADA SUVr) and longitudinal cognitive assessment (average follow-up: 4.1 ± 3.5 years). AD-related plasma biomarkers were measured with Simoa. Discriminative performance (AUC) of each marker was compared using ROC analysis, and combined utility was assessed with logistic regression. Subsequently, cutoffs were established aiming for 90%-specificity, to regroup participants into a plasma-based staging scheme. Age-, sex- and education-adjusted linear mixed models (LMM) were performed to compare associations of plasma versus PET-based staging with longitudinal cognition.</p><p><strong>Results: </strong>27 participants were A-T_{PET_low}, 22 A+T_{PET_low}, 27 A+T_{PET_int} and 29 A+T_{PET_high}. To discriminate A-T_{PET_low} participants from A+T_{PET_low/int} participants, P-tau217 performed best among all measured markers P-tau217, P-tau181, Aβ42/40, GFAP and NfL (AUC = 0.92 [95% CI: 0.856-0.985]). To discriminate A+T_{PET_high} participants from A+T_{PET_low/int} participants, also P-tau217 performed best among all markers (AUC = 0.74 [95% CI: 0.618-0.862]). A combination of Wald's backward-selected plasma markers did not statistically improve discriminative performance (DeLong's p > 0.05; two-marker combinations selected). Applying two cutoffs for P-tau217 as well as for the two-marker combinations, at 90% specificity to discriminate subsequent groups, we derived two plasma-based staging schemes. While the tau-PET staging scheme significantly and consistently associated with cognitive performance and decline across cognitive domains in LMMs, the plasma staging schemes did not.</p><p><strong>Conclusions: </strong>Performance of plasma-based staging approaches developed in this study were high when discriminating individuals without amyloid pathology, while this was moderate when discriminating amyloid positive individuals with a high tau-PET burden. Our LMM findings visualize that tau staging in amyloid-positive individuals remains optimally performed with tau-PET scans.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking cessation duration and risk of Alzheimer's disease: a nationwide cohort study in Korea.","authors":"Seong-Ho Moon, Min-Ho Kim, Jae-Hong Ryoo","doi":"10.1186/s13195-026-02132-2","DOIUrl":"10.1186/s13195-026-02132-2","url":null,"abstract":"<p><strong>Background: </strong>Smoking is a modifiable risk factor for Alzheimer's disease, yet the temporal pattern of risk reduction following smoking cessation remains unclear. We investigated whether Alzheimer's disease risk declines according to the duration of sustained smoking cessation in a large nationwide cohort.</p><p><strong>Methods: </strong>Using the Korean National Health Insurance Service database (2002-2023), we identified 1,403,636 adults with stable longitudinal smoking patterns based on repeated biennial health examinations. Smoking status was classified as never smokers, current smokers, or sustained quitters, with cessation duration categorised into 2-year intervals (< 2, 2-3, 4-5, 6-7, ≥ 8 years). Incident Alzheimer's disease was defined as at least two separate NHIS insurance claims. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals, adjusting for demographic, lifestyle, and metabolic factors.</p><p><strong>Results: </strong>During a mean follow-up of 10.5 years, 58,519 incident Alzheimer's disease cases were identified. Compared with current smokers, sustained quitters exhibited progressively lower hazards of Alzheimer's disease with increasing duration of abstinence, demonstrating a dose-response pattern. Individuals who had quit for < 2 years showed a risk reduction relative to current smokers (adjusted HR 0.899; 95% CI 0.819-0.986), while those with ≥ 8 years of abstinence had substantially lower risk (adjusted HR 0.582; 95% CI 0.423-0.801). When referenced to never smokers, those with < 2 years of abstinence retained excess risk, whereas cessation for ≥ 2 years was associated with Alzheimer's disease risk approaching that of never smokers.</p><p><strong>Conclusions: </strong>Sustained smoking cessation was associated with a graded reduction in Alzheimer's disease risk, with approximately 2 years of abstinence needed to approach never-smoker risk.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lecanemab in practice: AI-derived MRI predictors of benefit and Amyloid Related Imaging Abnormalities (ARIA).","authors":"Noa Bregman, Nuno Pedrosa de Barros, Talya Nathan, Mori Hay Levy, Diana Sima, Simon Van Eyndhoven, Aya Bar-David, Orna Aizenstein, Dana Niry, Lilian Atlan, Anan Abu Awad, Elissa Ash, Nurit Omer, Tamara Shiner","doi":"10.1186/s13195-026-02127-z","DOIUrl":"10.1186/s13195-026-02127-z","url":null,"abstract":"<p><strong>Introduction: </strong>Lecanemab, a monoclonal antibody targeting amyloid beta, has demonstrated meaningful clinical benefits in early Alzheimer's disease (AD), yet real-world data is needed to optimize patient selection and enhance safety monitoring, particularly with respect to amyloid-related imaging abnormalities (ARIA). Integration of quantitative and AI-derived MRI biomarkers may improve risk stratification and prediction of clinical trajectory.</p><p><strong>Methods: </strong>We conducted a retrospective real-world study of eighty-two patients with biomarker-confirmed early AD who initiated lecanemab at Tel Aviv Sourasky Medical Center between November 2023 and June 2025. Baseline MRI included volumetric T1-weighted imaging and susceptibility-weighted imaging (SWI). Automated whole-brain, regional cortical, and hippocampal volumes, and percentiles were extracted using FDA-cleared AI tools (icobrain by icometrix). Microhaemorrhage (MH) burden was assessed by both human and AI-assisted reads. Cognitive outcomes were evaluated using change in Mini-Mental State Examination (MMSE). Linear regression models assessed MRI predictors of cognitive response, and multivariable logistic regression identified predictors of ARIA.</p><p><strong>Results: </strong>Patients exhibited significantly lower cerebral volumes at treatment initiation. Mean whole brain percentile, mean gray-matter (GM) percentile, and mean white matter percentile were 11.45%, 8.6% and 38% respectively. Higher baseline GM volume predicted less MMSE decline at 12 months (β = 0.64, FDR-corrected p < 0.003). Hippocampal and white-matter volumes were not associated with cognitive outcomes. Seventeen patients (20.7%) developed ARIA. Baseline MH burden was the strongest predictor of ARIA (human rated OR=3.48 per MH, p=0.015, icobrain rated OR=3.25, p=0.01), while APOE ε4 carriage showed a strong directional trend which did not reach significance. Aspirin use and hypertension were not associated with ARIA. Agreement between icobrain and experts for MH ratings was excellent with a single-measure intraclass correlation coefficient (ICC) of 0.89 (95% CI: 0.83-0.93).</p><p><strong>Conclusions: </strong>AI-derived MRI markers, particularly GM volume and MH burden, provide valuable predictors of cognitive response and ARIA risk in patients treated with lecanemab. Integrating quantitative neuroimaging into clinical workflows may enhance personalized treatment decisions and improve real-world implementation of Amyloid-targeting therapies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facial phenotypes in Alzheimer's disease: from neurobiology to artificial intelligence.","authors":"Wenshan Sun, Rong Xing, Jian Zhou, Yong Li, Gelin Xu","doi":"10.1186/s13195-026-02129-x","DOIUrl":"10.1186/s13195-026-02129-x","url":null,"abstract":"<p><p>Facial analysis is increasingly being explored as a source of scalable behavioral signals relevant to Alzheimer's disease (AD) and AD-related cognitive impairment. In this narrative review, informed by a structured literature search, we summarize current evidence on the biological and behavioral basis of facial alterations in AD, with particular emphasis on affective expressivity, neuropsychiatric manifestations, and dynamic facial behavior. We also review representative artificial intelligence-based facial analysis methods, including commonly used datasets, feature representations, and modeling strategies, ranging from facial landmarks and texture descriptors to spatiotemporal video models, multimodal fusion, and language-enhanced frameworks. Current evidence remains limited by small and largely single-center cohorts, heterogeneity in acquisition settings and outcome definitions, inadequate control of confounding factors, limited external validation, poor calibration reporting, and persistent concerns regarding interpretability and clinical specificity. Within the evolving biomarker-based diagnostic framework of AD, facial analysis is better viewed as a candidate, non-specific, and context-dependent tool for auxiliary risk stratification, triage support, and longitudinal monitoring rather than as stand-alone diagnostic tests. Future progress will depend on standardized data acquisition, integration with clinical and biomarker data, improved explainability, and prospective real-world validation.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and molecular determinants of medial temporal lobe network vulnerability in aging and Alzheimer's disease.","authors":"Elise Saul, Léa Chauveau, Brigitte Landeau, Jade Lasserve, Blandine Montagne, Emilie Foyard, Géraldine Poisnel, Gaël Chételat, Robin de Flores","doi":"10.1186/s13195-026-02125-1","DOIUrl":"10.1186/s13195-026-02125-1","url":null,"abstract":"<p><strong>Background: </strong>The medial temporal lobe is organized into two memory-critical networks: the anterior-temporal and posterior-medial systems. While these systems show selective vulnerability to aging and Alzheimer's disease, the underlying structural and molecular determinants of this susceptibility remain unclear. We aimed to characterize the specific white matter pathways supporting these networks, investigate how amyloid-β and neuroinflammation interact to impact their integrity, and determine if structural changes relate to functional connectivity alterations.</p><p><strong>Methods: </strong>In 88 cognitively unimpaired (CU) older adults (≥ 65 years) from the Age-Well cohort (NCT02977819), we combined longitudinal diffusion MRI tractography, resting-state fMRI, amyloid-β PET (Florbetapir), and plasma glial fibrillary acidic protein (GFAP). We reconstructed fiber pathways of the perirhinal (anterior-temporal system hub) and parahippocampal (posterior-medial system hub) cortices and quantified their microstructural integrity, network connectivity, and relationships to pathology.</p><p><strong>Results: </strong>The anterior-temporal and posterior-medial systems relied on partly distinct structural pathways. Both involved the inferior longitudinal and cingulum bundles, but the anterior-temporal system was specifically associated to their inferior portions, as well as thalamic radiations, and callosal fibers, whereas the posterior-medial system relied more on their superior portions and the inferior fronto-occipital fasciculus. We identified a non-linear, inverted U-shaped association between pathway integrity and amyloid-β burden, suggesting dynamic structural changes across early pathological stages. Crucially, plasma GFAP moderated this relationship for the posterior-medial pathway: the negative impact of amyloid-β on structural integrity was exacerbated in individuals with higher astroglial reactivity, highlighting a synergistic pathological effect. Finally, in high amyloid-β individuals, increased anterior-temporal functional connectivity correlated with lower anterior-temporal pathway integrity, suggesting that network higher FC may represent a maladaptive response to early amyloid-β deposition leading to white matter integrity loss.</p><p><strong>Conclusions: </strong>Together, our findings reveal distinct mechanisms of vulnerability within medial temporal networks: while the posterior-medial system is primarily sensitive to the synergistic effects of amyloid-β and astroglial reactivity, the anterior-temporal system shows lower structural integrity linked to higher FC in the presence of amyloid. By providing a mechanistic framework for these early disruptions, this study advances the understanding of preclinical Alzheimer's disease and identifies specific structural-functional signatures that could serve as sensitive biomarkers for targeted interventions.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural changes after computerized cognitive training in coronary heart disease with mild cognitive impairment: secondary analysis of a randomized clinical trial.","authors":"Yi Ye, Danyang Wang, Jiayi Han, Shiyi Li, Manlei Chen, Yueling Sun, Fangjiang Li, Hongsen Tian, Le Wang, Wei Zhao, Xinhui Ning, Qing Chen, Xiaoyi Wang, Changsheng Ma, Xiaoping Liu, Yong Zeng","doi":"10.1186/s13195-026-02116-2","DOIUrl":"https://doi.org/10.1186/s13195-026-02116-2","url":null,"abstract":"<p><strong>Background: </strong>Mild cognitive impairment (MCI) is prevalent in patients with coronary heart disease (CHD) and has been linked to alterations in memory-related brain networks. Although computerized cognitive training (CCT) may enhance cognition by promoting neuroplasticity. It remains unknown whether multidomain adaptive CCT can induce structural and functional plasticity within specific memory circuits in patients with CHD and MCI, and whether such neural changes relate to cognitive and cardiovascular outcomes.</p><p><strong>Methods: </strong>In this secondary analysis of a multicenter, randomized trial, CHD patients with MCI received either multidomain adaptive CCT or basic CCT as active control. Multimodal MRI, cognitive testing, and blood pressure measurement were conducted at baseline after 12-week intervention. Outcome measures were functional connectivity (FC) of the two memory-related networks included the Parietal Memory Network (PMN) and Context Association Network (CAN), grey matter volume as well as structural connectivity of their key regions, and the association of FC changes with cognitive and blood pressure changes.</p><p><strong>Results: </strong>A total of 185 participants (95 in the adaptive CCT group, 90 in the active control group) were eligible. The multidomain training significantly increased hypothesis-driven outcomes, including within-memory network FC (left CAN: p = 0.045; right CAN: p = 0.031; left PMN: p = 0.028) and right PMN whole-brain connectivity (p = 0.010). Exploratory analysis revealed that training-induced FC increased between PMN/CAN and multiple other networks (p_FDR < 0.05). Multidomain CCT also increased grey matter volume in the right precuneus (p = 0.048) and parahippocampal cortex (p = 0.032), and strengthened structural connectivity in the right precuneus-inferior parietal lobule (p = 0.016) and parahippocampal-superior frontal gyrus (p = 0.044) pathways. Improvements in global cognition and working memory were positively associated with changes in FC of PMN (β = 0.23 to 0.36, ps < 0.05) in treatment group. Reductions in systolic blood pressure and pulse pressure were linked to changes in FC of right PMN ([Formula: see text] = -0.25 to 0.31, ps < 0.05), and mediation analyses indicated that FC of right PMN and the cingulo-opercular networks mediated the treatment effect on pulse pressure (p = 0.040).</p><p><strong>Conclusions: </strong>Multidomain adaptive CCT promotes functional and structural neuroplasticity in memory-related circuits in CHD patients with MCI. The alterations in functional connectivity were linked to cognitive gains and appeared to mediate the reduction in blood pressure as a modifiable cardiovascular risk factor, indicating that CCT may engage in the brain-heart axis.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT05735041; Registered on Jan. 18, 2023.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}