Alzheimer's Research & Therapy最新文献

{"title":"Age-dependent diagnostic and correlational architecture of multiplex plasma biomarkers in Alzheimer's disease: a cross-ethnic, cross-platform validation study.","authors":"Boru Jin, Aitong Li, Fengling Xu, Cong Chen, Jiawen Dong, Jingjing Wang, Dantong Tang, Ying Gu, Huayan Liu","doi":"10.1186/s13195-026-02119-z","DOIUrl":"10.1186/s13195-026-02119-z","url":null,"abstract":"<p><strong>Background: </strong>Plasma phosphorylated tau-217 (p-tau217) is one of the most accurate blood-based biomarkers for Alzheimer's disease (AD), yet whether its diagnostic and correlational properties vary with age at onset has not been systematically examined.</p><p><strong>Methods: </strong>We measured eight plasma biomarkers (tau, amyloid, neurodegeneration, neuroinflammation) via automated chemiluminescence immunoassay in a Chinese memory clinic cohort (n = 604; amyloid positron emission tomography (PET) reference), with validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1,615; amyloid and tau PET). Diagnostic accuracy and biomarker-clinical correlations were compared between early-onset (EO < 65 years) and late-onset (LO ≥ 65 years) subgroups.</p><p><strong>Results: </strong>Overall accuracy was high (primary area under the curve (AUC) 0.923; ADNI 0.904). In ADNI, p-tau217 showed higher accuracy in EO than LO (AUC 0.940 vs 0.892, P = 0.012), most pronounced at age 60 and absent by 70. The optimal biomarker shifted from tau-centric markers in LO to Aβ42/Aβ40 in EO. Tau biomarker-clinical correlations diverged sharply by onset age and were stronger in EO for cognitive and neuropsychiatric outcomes, whereas glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) showed no age-dependent heterogeneity. Opposing-direction associations were observed for p-tau217%, which correlated negatively with onset age in AD but positively in Non-AD cognitive impairment. In an exploratory analysis, baseline p-tau217 was associated with longitudinal cognitive decline, numerically greater in EO though based on a small subgroup. Cross-ethnic generalizability was supported by the ADNI-Asian subgroup.</p><p><strong>Conclusions: </strong>This cross-ethnic, cross-platform study demonstrates that the diagnostic accuracy, biomarker-clinical correlation architecture, and optimal analyte selection of plasma p-tau217 vary systematically with age at onset, most markedly for tau-related measures. These findings challenge universal threshold paradigms and support age-stratified biomarker interpretation in clinical practice and therapeutic trial design.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325277","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":"Clinico-biological trajectories stratified by combined tau biomarkers in preclinical Alzheimer's disease.","authors":"Miguel A Labrador-Espinosa, Nicolai Franzmeier, Stamatia Karagianni, Alexis Moscoso, Michael Schöll","doi":"10.1186/s13195-026-02123-3","DOIUrl":"10.1186/s13195-026-02123-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Tau pathology biomarkers provide prognostic indicators of neurodegeneration and cognitive decline in Alzheimer's disease (AD), making them crucial to early patient stratification for disease-modifying interventions. Plasma p-tau217 indexes early tau pathophysiology, whereas FDA/EMA-approved [&lt;sup&gt;18&lt;/sup&gt;F]flortaucipir PET (tau-PET) visual assessments indicate advanced neurofibrillary tangle pathology. Here, we identified concordant and discordant profiles based on combined plasma p-tau217 status and tau-PET visual assessments in cognitively unimpaired amyloid-β (Aβ)-positive older adults and investigated whether these profiles delineate distinct longitudinal trajectories of Aβ and tau accumulation, neurodegeneration, and cognitive decline.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We included 330 cognitively unimpaired Aβ-PET-positive participants (72.2 ± 4.8 years; 58% female; 48% randomized to receive solanezumab) from the A4 Study, who underwent plasma p-tau217 and tau-PET at baseline. Plasma positivity (T&lt;sub&gt;1&lt;/sub&gt; +) followed A4 core criteria as previously reported (≥ 0.28 U/mL), while tau-PET positivity (T&lt;sub&gt;2&lt;/sub&gt; +) was determined by three expert visual readers with strong inter-rater agreement (κ = 0.954). Participants were stratified as T&lt;sub&gt;1&lt;/sub&gt;[- / +]T&lt;sub&gt;2&lt;/sub&gt;[- / +] at baseline and were followed for 5.0 ± 1.7 years. Baseline and longitudinal differences in regional Aβ- and tau-PET SUVR, MRI-measured gray-matter (GM) volume, and cognitive performance were examined using ANCOVA and mixed-effects models. All models accounted for treatment, with additional sensitivity analyses excluding treated participants.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;At baseline, 57% were negative-concordant (T&lt;sub&gt;1&lt;/sub&gt; - T&lt;sub&gt;2&lt;/sub&gt; - : n = 187), 24% were discordant (T&lt;sub&gt;1&lt;/sub&gt; + T&lt;sub&gt;2&lt;/sub&gt; - : n = 53; T&lt;sub&gt;1&lt;/sub&gt; - T&lt;sub&gt;2&lt;/sub&gt; + : n = 27), and 19% were positive-concordant (T&lt;sub&gt;1&lt;/sub&gt; + T&lt;sub&gt;2&lt;/sub&gt; + : n = 63). T&lt;sub&gt;1&lt;/sub&gt; + T&lt;sub&gt;2&lt;/sub&gt; + profile constituted the highest-risk state, showing the greatest baseline cortical Aβ burden, the strongest neocortical tau progression (fronto-temporo-parietal pattern; p(FDR) &lt; 0.05), marked baseline atrophy with accelerated longitudinal GM loss in overlapping regions, and the fastest cognitive decline (PACC: d = -1.84, p &lt; 0.001). Consistently, T&lt;sub&gt;1&lt;/sub&gt; + T&lt;sub&gt;2&lt;/sub&gt; + exhibited the highest hazard of progression to more advanced clinico-biological stages over follow-up (HR&lt;sub&gt;Clinical&lt;/sub&gt; = 3.03, HR&lt;sub&gt;Biological&lt;/sub&gt; = 9.98; p &lt; 0.001). Discordant profiles showed comparatively limited progression, suggesting earlier or low-tau states. Results were essentially unchanged after excluding treated participants.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Integrating plasma p-tau217 with tau-PET visual assessment reveals clinically meaningful tau-biomarker heterogeneity in preclinical AD. Our findings highlight the value of combining these biomarkers to refine early ri","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306769","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":"Outer nuclear layer thinning as an in vivo biomarker for discriminating probable FTLD-tau from probable FTLD-TDP with PET-supported subtyping.","authors":"Zhengxi Zhang, Qinqin Zhang, Yang Chen, Ruijie Zeng, Meizhen Min, Haolun Sun, Yujie Lai, Yingying Shen, Yuting Yang, Ming Feng, Zi Jin, Ying Zhang, Hebei Gao, Fan Lu, Yan-Jiang Wang, Meixiao Shen","doi":"10.1186/s13195-026-02111-7","DOIUrl":"10.1186/s13195-026-02111-7","url":null,"abstract":"<p><strong>Background and objectives: </strong>Outer nuclear layer (ONL) thinning has been identified in frontotemporal lobar degeneration (FTLD); however, its utility for distinguishing the subtypes of FTLD-tauopathy (FTLD-tau) and TDP-43 proteinopathy (FTLD-TDP) remains unknown. We investigated whether ONL thickness provides a subtype-informative retinal signal for differentiating PET-supported probable FTLD-tau (pFTLD-tau) from probable FTLD-TDP (pFTLD-TDP) in vivo.</p><p><strong>Methods: </strong>Patients clinically diagnosed with FTLD were subtyped into pFTLD-tau and pFTLD-TDP groups based on multimodal PET and clinical criteria. Normal controls (NCs) were cognitively unimpaired on standardized testing and clinical evaluation. Macular images were acquired using swept-source OCT. A custom deep learning algorithm segmented the retina into eight sublayers. The thickness of each retinal sublayer was assessed across the eight sectors of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Retinal thickness differences were analyzed using generalized estimating equations, and exploratory discrimination models were evaluated using age- and sex-adjusted stepwise logistic regression with apparent and bootstrap optimism-corrected AUCs reported. Exploratory partial correlation analysis was conducted to examine the associations between ONL thickness and cognitive scores.</p><p><strong>Results: </strong>A total of 86 participants were included (21 pFTLD-tau, 27 pFTLD-TDP and 38 NCs). Widespread ONL thinning was observed in pFTLD-tau (Cohen's d= -0.753 to -1.268 vs. controls; -0.666 to -1.069 vs. pFTLD-TDP; all FDR-adjusted P < 0.05), while ONL in pFTLD-TDP remained preserved. A model combining retinal nerve fiber layer (RNFL), ONL, and myoid-ellipsoid zone (MEZ) thickness showed exploratory discrimination for differentiating pFTLD-tau from pFTLD-TDP (apparent AUC, 0.922; optimism-corrected AUC, 0.866). The outer thickness model yielded higher AUC estimates than the inner thickness model (0.884/0.835 vs. 0.713/0.630), and the individual ONL model showed moderate exploratory discrimination (0.808/0.765). ONL thickness was correlated with cognitive scores in pFTLD-tau (partial r = 0.433-0.483; all P < 0.05), whereas corresponding associations in pFTLD-TDP did not reach statistical significance.</p><p><strong>Discussion: </strong>ONL thinning was preferentially observed in pFTLD-tau and contributed to exploratory discrimination between PET-supported probable FTLD subtypes. These findings suggest that ONL thickness may provide complementary, noninvasive information for probable FTLD subtype stratification, with potential to facilitate therapeutic trial enrollment and personalized management. Future studies incorporating neuropathological confirmation and fluid biomarkers are warranted to validate these findings.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306802","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":"Real-world effectiveness of monoclonal antibody lecanemab versus acetylcholinesterase inhibitors in Alzheimer's disease: a target trial emulation.","authors":"Chuo-Yu Lee, Chih-Wei Hsu, Ping-Tao Tseng, Yi-Ya Fang, Brendon Stubbs, Trevor Thompson, Andre F Carvalho, Yu-Hsuan Lin, Yu-Chen Kao, Fu-Chi Yang, Tien-Wei Hsu, Chih-Sung Liang","doi":"10.1186/s13195-026-02095-4","DOIUrl":"https://doi.org/10.1186/s13195-026-02095-4","url":null,"abstract":"<p><strong>Background: </strong>Acetylcholinesterase inhibitors (AChEIs) provide symptomatic relief in Alzheimer's disease (AD), whereas lecanemab may modify disease progression; however, real-world evidence on its safety and clinical impact remains limited. Therefore, this study aimed to compare the safety and effectiveness of initiating lecanemab versus AChEIs in patients with mild cognitive impairment (MCI) or AD.</p><p><strong>Methods: </strong>Using the TriNetX US electronic health record network, we conducted a retrospective cohort study including individuals diagnosed with MCI or AD between July 2023 and September 2025. A target trial emulation with 1:1 propensity score matching and Cox models estimated comparative risks.</p><p><strong>Results: </strong>Lecanemab was associated with a fivefold higher incidence of neuroimaging abnormalities than AChEIs, while 1-year treatment persistence was similar (53.4% vs 52.5%). After matching, 589 patients were included in each cohort. Compared with AChEIs, lecanemab was associated with significantly lower risks of behavioral and psychological symptoms of dementia (BPSD) (HR, 0.52; 95% CI, 0.36-0.77) and emergency visits (HR, 0.66; 95% CI, 0.51-0.85), but a higher risk of hospitalization (HR, 1.31; 95% CI, 1.03-1.67). Lecanemab was also associated with lower use of antipsychotics (HR, 0.47; 95% CI, 0.32-0.70), antidepressants (HR, 0.60; 95% CI, 0.43-0.85), melatonin/orexin antagonists (HR, 0.61; 95% CI, 0.42-0.88), antibiotics (HR, 0.61; 95% CI, 0.44-0.86), and antifungals (HR, 0.57; 95% CI, 0.37-0.88), whereas steroid use was higher among lecanemab users (HR, 2.19; 95% CI, 1.55-3.10).</p><p><strong>Conclusions: </strong>Compared with an AChEI-based conventional care strategy, lecanemab initiation was associated with comparable treatment persistence and lower observed risks of BPSD, emergency visit as well as reduced use of psychotropic and infection-related medications in exploratory analyses. However, the higher incidence of neuroimaging abnormalities associated with lecanemab, along with increased risks of hospitalization and corticosteroid use, likely reflects proactive clinical monitoring and management of amyloid-related imaging abnormalities (ARIA). While residual confounding cannot be excluded and results warrant cautious interpretation, these exploratory findings warrant further validation in biomarker-confirmed cohorts and head-to-head randomized trials.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300370","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}

{"title":"HDAC7 acts as an astrocytic mediator of Aβ pathology that directly engages IKK to drive astrocyte neurotoxicity and neurodegeneration in Alzheimer's disease.","authors":"Jinwang Ye, Yunsong Deng, Bingge Zhang, Chengjia Li, Xing Guo, Ruizhu Yue, Huali Wan, Yue Hao, Shifeng Xiao","doi":"10.1186/s13195-026-02121-5","DOIUrl":"10.1186/s13195-026-02121-5","url":null,"abstract":"<p><strong>Background: </strong>Astrocytes undergo reactive transformations in response to pathological stimuli and play a critical role in neuronal loss associated with Alzheimer's disease (AD). However, the intrinsic mechanisms through which astrocytes detect amyloid-β (Aβ) pathology and develop neurotoxic properties remain inadequately understood. The dysregulation of class IIa Histone deacetylases (HDACs) has been implicated in astrocyte dysfunction under pathological conditions. This study aims to elucidate the role of HDAC7 as an astrocytic mediator of Aβ that drives the formation of neurotoxic reactive astrocytes, and to propose HDAC7 as a potential therapeutic target for mitigating neuronal loss and cognitive deficits in AD.</p><p><strong>Methods: </strong>We examined HDAC7 expression in APP/PS1 mice of varying ages using RT-qPCR, Western blotting, and immunostaining analysis. Astrocyte-specific HDAC7 overexpression and knockdown were achieved through adeno-associated virus (AAV) delivery (GfaABC1D promoter) in wild-type (WT) and APP/PS1 mice, followed by behavioral tests, immunostaining, RT-qPCR, and RNA-seq. Mechanistic studies were conducted using primary astrocytes derived from WT and Hdac7^flx/flx mice, employing co-immunoprecipitation, Western blotting, and neuron viability assays. Pharmacological inhibition of HDAC7 in APP/PS1 mice was performed via intraperitoneal injection of TMP195, and the effects on neurotoxic reactive astrocytes, neuronal and synaptic loss, and behavioral performance were measured.</p><p><strong>Results: </strong>HDAC7 was selectively upregulated in plaque-adjacent astrocytes in APP/PS1 mice. Overexpression of HDAC7 specifically in astrocytes was sufficient to induce a neurotoxic transcriptional profile, neuronal loss, and cognitive deficits in both WT and young APP/PS1 mice. Mechanistically, upon Aβ stimulation, the upregulated HDAC7 directly interacted with and deacetylated IKKα and IKKβ, resulting in the activation of IKK, translocation of NF-κB to the nucleus, and subsequent expression of neurotoxic genes. This neurotoxic conversion was dependent on IKK activity, as IKK inhibition nullified the effects in astrocytes overexpressing HDAC7. Conversely, astrocytic HDAC7 knockdown or treatment with TMP195 attenuated IKK-NF-κB signaling, reduced the presence of neurotoxic reactive astrocytes, and rescued neurodegeneration and cognitive deficits in APP/PS1 mice.</p><p><strong>Conclusions: </strong>HDAC7 acts as an intrinsic effector within astrocytes, responding to Aβ pathology and converting astrocytes into a neurotoxic state through direct interaction with IKK. Targeting HDAC7 presents a promising strategy for astrocyte-directed therapeutic interventions in Alzheimer's disease.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300638","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 prevalence and incidence of young onset dementia in the Netherlands: a prospective study in two catchment areas.","authors":"Hanna E Bodde, Jackie M Poos, Guillaume H P R Kolman, Angeline Bosman, Sten P Willemsen, Kirsten Peetoom, Yolande A L Pijnenburg, Raymond Koopmans, Frans R J Verhey, Marjolein E de Vugt, Christian Bakker, Janne M Papma","doi":"10.1186/s13195-026-02120-6","DOIUrl":"10.1186/s13195-026-02120-6","url":null,"abstract":"<p><strong>Background: </strong>Young-onset dementia (YOD), defined as dementia with symptom onset before the age of 65, is associated with distinct and often complex care needs that differ from those with late-onset dementia. Current national data on YOD incidence, prevalence, and demographic characteristics are limited, underscoring the importance of prospective studies to inform policy and tailored care services.</p><p><strong>Methods: </strong>We conducted two prospective one-year prevalence and incidence studies using active case-finding in two Dutch catchment areas, one urban and one more rural region, between 2020 and 2022. Individuals with YOD making use of care services were registered in an online database. Data on dementia subtype, living situation, and migration background were collected to explore regional variation.</p><p><strong>Results: </strong>We identified 372 individuals with YOD in the urban Rotterdam area, and 209 in the more rural Eindhoven-De Kempen area. Age-standardized prevalence per 100,000 individuals, standardized to the Dutch population, was 77.3 in the Rotterdam region, and 66.1 in the Eindhoven-De Kempen region for ages 30-69 years, and 46.3 and 36,9, respectively, for ages 30-64 years. Corresponding age-standardized incidence rates were 24.2 and 23.5 for ages 30-69 years, and 13.9 in both regions for ages 30-64 years. Alzheimer's disease was the most common diagnosis in both areas. Compared with Eindhoven-De Kempen, the Rotterdam region had significantly more vascular dementia cases (p < 0.05 for incidence, and p < 0.001 for prevalence) and longer diagnostic delays (2.2 vs. 1.3 years between first GP consultation and diagnosis). Most individuals lived at home (76.4% and 85.4% resp. in Rotterdam and Eindhoven-De Kempen) and 30.8% in Rotterdam and 12.5% in Eindhoven-De Kempen had a migration background. Extrapolation of incidence figures suggests that between 14,655 and 20,340 individuals were living with YOD in the Netherlands in 2021.</p><p><strong>Conclusions: </strong>This study estimates the number of people living with YOD in the Netherlands. In addition, our findings show regional variation in dementia subtypes, a high proportion of people with YOD living at home, and a substantial proportion of people with YOD with a migration background. These insights underline the importance of region‑specific, person‑centered, culture sensitive YOD care at home.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300414","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":"Characterizing the MRI signature of hippocampal sclerosis of aging.","authors":"Gustaf Rådman, Amanda E Denning, Sadhana Ravikumar, Nicola Spotorno, Ranjit Ittyerah, Lisa M Levorse, John L Robinson, Theresa Schuck, Sydney A Lim, Eunice Chung, Madigan Bedard, Winifred Trotman, Alejandra Bahena, María Del Mar Arroyo-Jiménez, Alicia Vela, Esther Buendia, Maria Mercedes Iñiguez de Onzoño Martin, María Pilar Marcos Rabal, Mónica Muñoz-López, Rosanna K Olsen, John A Detre, Edward B Lee, David A Wolk, Daniel T Ohm, Corey T McMillan, Ricardo Insausti, David J Irwin, Paul A Yushkevich, Laura E M Wisse","doi":"10.1186/s13195-026-02118-0","DOIUrl":"10.1186/s13195-026-02118-0","url":null,"abstract":"<p><strong>Background: </strong>Hippocampal sclerosis of aging (HS-A), a common cause of dementia, can currently only be diagnosed at autopsy. We aimed to identify and evaluate MRI metrics to distinguish HS-A from Alzheimer's Disease neuropathologic change (ADNC) and cases with limited/no pathology.</p><p><strong>Methods: </strong>HS-A (N = 5), ADNC (N = 10), and limited/no pathology (N = 12) cases were compared on postmortem MRI signatures: manually measured cornu ammonis (CA)1/subiculum thickness, grey matter signal intensity, and automated hippocampal subfield thickness metrics. Similar metrics were obtained in T₁-weighted antemortem MRI in an initial dataset (HS-A = 4, ADNC = 7, limited/no pathology = 25) for group differences and discrimination (HS-A vs ADNC). T₁-weighted metrics were then evaluated in a second dataset (HS-A = 6, ADNC = 18) and in a pooled post-hoc analysis combining HS-A and ADNC cases from both datasets (N_HS-A = 10, N_ADNC = 25).</p><p><strong>Results: </strong>Postmortem MRI showed hippocampal thinning and grey matter hypointensity in HS-A at the CA1-subiculum junction more severe than in ADNC and limited/no pathology cases. In antemortem MRI, differentiating HS-A and ADNC based on anterior/posterior manual measures of CA1/subiculum thickness and hippocampal volumes displayed good discrimination in dataset 1, but lower discriminative performance in dataset 2. In complementary analyses pooling both datasets and adjusting for age, manual thickness achieved good performance (area under the curve (AUC) = 0.80-0.87), while anterior, posterior, and whole hippocampal volumes showed excellent discrimination (AUC = 0.94-0.98).</p><p><strong>Limitations: </strong>The study included a relatively small and neuropathologically heterogeneous sample. The final antemortem analyses were exploratory, reflecting challenges in replicating findings across independent datasets. Classification was limited to HS-A and ADNC, leaving it uncertain how the metrics perform when comparing HS-A with other diagnostic groups. HS-A diagnoses were determined postmortem, often several years after MRI, and most measures relied on standard imaging sequences with limited resolution to assess fine-grained hippocampal subfields.</p><p><strong>Conclusions: </strong>HS-A displays distinct changes in the hippocampus that are detectable through structural MRI. Associated quantifiable MRI metrics may serve as promising tools in aiding antemortem HS-A diagnosis but require further validation in larger cohorts and against other dementia-related diseases.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300395","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":"Virtual brain and electroencephalography explain the variance of memory alterations in mild cognitive impairment.","authors":"Anita Monteverdi, Matteo Cotta Ramusino, Francesca Conca, Alberto Augello, Chiara Totaro, Paolo A Grasso, Anna Castelnovo, Roberta M Lorenzi, Michele Terzaghi, Lisa M Farina, Alfredo Costa, Anna Pichiecchio, Stefano F Cappa, Claudia Gandini Wheeler-Kingshott, Fulvia Palesi, Egidio D'Angelo","doi":"10.1186/s13195-026-02114-4","DOIUrl":"10.1186/s13195-026-02114-4","url":null,"abstract":"<p><strong>Background: </strong>Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive.</p><p><strong>Methods: </strong>Here Aβ/tau biomarkers were used to distinguish positive (MCI⁺- prodromal Alzheimer's disease) and negative (MCI^-) subjects in a cohort of 30 MCI patients (18 MCI⁺ and 12 MCI^-). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance.</p><p><strong>Results: </strong>While virtual brain simulations did not reveal E/I differences between MCI⁺ and MCI^-, a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI⁺ largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert.</p><p><strong>Conclusions: </strong>This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293082","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":"Myelin-driven structural network redundancy underlies cognition in cerebral small vessel disease.","authors":"Yage Qiu, Wentao Hu, Yao Wang, Qingyang Fu, Ying Hu, Qun Xu, Hongjiang Wei, Yan Zhou, Yawen Sun","doi":"10.1186/s13195-026-02115-3","DOIUrl":"10.1186/s13195-026-02115-3","url":null,"abstract":"<p><strong>Background: </strong>White matter hyperinxtensity (WMH) and normal-appearing white matter (NAWM) are critical markers for tracking disease progression in cerebral small vessel disease (CSVD), indicative of a spectrum of white matter injury. The core pathological alteration underlying such injury is the disruption of myelin integrity and loss of axons. We hypothesized that the myelin content in WMH and NAWM may exert distinct effects on brain networks and cognition in CSVD.</p><p><strong>Methods: </strong>A total of 129 diagnosed CSVD patients were retrospectively enrolled. Myelin content was assessed with sub-voxel precision using iterAtive magnetic suscePtibility sources sepARaTion Quantitative Susceptibility Mapping (APART-QSM). Structural network redundancy was derived from diffusion tensor imaging (DTI). WMH and NAWM masks were generated. Associations between WMH/NAWM myelin content, structural network redundancy, and cognitive performance were examined using partial correlation and mediation analyses.</p><p><strong>Results: </strong>Myelin content was significantly higher in NAWM than in WMH. Decreased structural network redundancy was significantly linked to myelin loss in NAWM but not in WMH. Moreover, redundancy indirectly linked NAWM myelin to cognition, whereas no such indirect pathway was observed for WMH myelin. No direct or total effect of myelin content on cognition was observed.</p><p><strong>Conclusions: </strong>These findings highlight the critical role of NAWM-related myelin integrity in preserving cognition through its association with structural network redundancy in CSVD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293135","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}

{"title":"Associations of plasma biomarkers of Alzheimer's disease pathology with modifiable risk factors and cognitive and functional outcomes: evidence from cross-sectional prediction and latent path analyses in the Bio-Hermes-001 cohort.","authors":"Megan Kirk, Joseph Kwon, Kalliopi Mavromati, Adam Gordon-Boyle, Kamaldeep Bhui, Ivan Koychev, Sarah Bauermeister, Apostolos Tsiachristas","doi":"10.1186/s13195-026-02106-4","DOIUrl":"10.1186/s13195-026-02106-4","url":null,"abstract":"<p><strong>Introduction: </strong>Plasma biomarkers of Alzheimer's Disease and Related Dementias (ADRD) pathology may help clarify associations between modifiable risk factors (MRFs) and cognitive and functional impairment.</p><p><strong>Methods: </strong>Cross-sectional data from 1002 adults (mean age 72.0 ± 6.7) enrolled in the Bio-Hermes-001 study were analysed. First, block regression models assessed the added predictive value of MRFs and ADRD plasma biomarkers on cognitive (Mini-Mental State Examination, [MMSE]) and functional outcomes (Functional Activities Questionnaire, [FAQ]), beyond MRFs alone. Second, latent path analysis (LPA) examined potential pathways linking MRFs, ADRD biomarkers, and cognition and functional outcomes.</p><p><strong>Results: </strong>ADRD biomarkers significantly improved prediction models for MMSE (ΔR² = 0.11) and FAQ scores (ΔR² = 0.11). Indirect effects consistent with mediation were observed for depression (B = -0.05), BMI (B = 0.02), and tobacco use (B = 0.14) in relation to cognitive and functional outcomes.</p><p><strong>Discussion: </strong>ADRD biomarkers are relevant to pathways linking MRFs with cognitive and functional outcomes and have potential for risk stratification and prevention research. Longitudinal studies are needed to determine temporal relationships and clarify potential causal mechanisms.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275595","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}