Alzheimer''s and Dementia: Translational Research and Clinical Interventions最新文献

{"title":"Integration of blood-based biomarkers and genomic variants identifies individuals with mild cognitive impairment who benefit from multidomain intervention","authors":"Tetsuaki Kimura,&nbsp;Akinori Nakamura,&nbsp;Taiki Sugimoto,&nbsp;Tomomi Satou,&nbsp;Naoyuki Sato,&nbsp;Shumpei Niida,&nbsp;Kouichi Ozaki,&nbsp;Takashi Sakurai,&nbsp;Hidenori Arai,&nbsp;Daichi Shigemizu,&nbsp;J-MINT study group","doi":"10.1002/trc2.70329","DOIUrl":"https://doi.org/10.1002/trc2.70329","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Our recent Japan-Multimodal Intervention Trial for the Prevention of Dementia (J-MINT) trial suggested that multidomain lifestyle interventions may delay cognitive decline. However, substantial interindividual variability in response persists, and identifying individuals more likely to benefit from the intervention remains challenging. Blood-based biomarkers (BBMs), which provide a minimally invasive means of assessing Alzheimer's disease (AD)-related pathological processes, may help identify biologically distinct subgroups of individuals with mild cognitive impairment (MCI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Blood-based biomarkers—including amyloid-β42/40 ratio, phosphorylated tau-217, neurofilament light chain, and glial fibrillary acidic protein (GFAP)—were measured in J-MINT participants. Hierarchical clustering based on BBM profiles was used to identify biologically defined subgroups. Whole-genome sequencing data were analyzed using genome-wide association analysis (GWAS) to identify genetic variants associated with the BBM-based subgroup. A prediction model for the subgroup assignment was constructed using the associated incorporating the genetic variants, age, sex, and apolipoprotein E4 (<i>APOE4)</i> allele count. Model performance was evaluated using five-fold cross-validation repeated 1000 times.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>BBM-based clustering identified a subgroup characterized by elevated GFAP and multiple biomarker abnormalities. Within this subgroup, the change in cognitive performance from baseline to 18 months differed significantly between intervention and control groups, with greater decline observed in the control group. GWAS identified four variants showing suggestive association with the subgroup, two of which were located in intronic regions of genes associated with hearing loss (<i>PCDH15</i> and <i>ATP11A</i>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>BBM-based clustering identified biologically distinct subgroups among individuals with MCI. The subgroup characterized by multiple biomarker abnormalities and elevated GFAP showed differential cognitive trajectories between the intervention and control groups. These findings suggest that BBMs, potentially in combination with genetic information, may help identify individuals with a more progressive AD-related biological profile who may derive greater benefit from multidomain intervention.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70329","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLP-1 receptor agonists in Alzheimer's disease and MCI: a meta-analysis","authors":"Ryan G. P. Siqueira,&nbsp;Carlotta Ranalli,&nbsp;Duygu Yılmaz,&nbsp;Meire da Silva,&nbsp;Bernardo Raposo Pinel Maltez,&nbsp;Giovanni Gosch Berton,&nbsp;Jeffrey L. Cummings","doi":"10.1002/trc2.70334","DOIUrl":"https://doi.org/10.1002/trc2.70334","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is the leading cause of dementia in older individuals and remains a major clinical and socioeconomic burden. Despite the success of anti-amyloid therapies in reducing biomarker burden, more effective and safer treatments are still needed. Given the emerging evidence of a role for metabolic dysfunction and brain insulin resistance in AD pathophysiology, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been proposed as potential disease-modifying therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We conducted a systematic review and meta-analysis of PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to April 22, 2026 to evaluate the efficacy and safety of GLP-1 RAs in AD and mild cognitive impairment. Randomized controlled trials comparing GLP-1 RAs with placebo, standard care, or non-intervention across the Alzheimer's continuum were eligible; abstracts and studies with unavailable results were excluded. Random-effects models were used. Risk ratios (RRs) were calculated for binary outcomes, and mean or standardized mean differences for continuous outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Seven studies comprising 4132 participants met the inclusion criteria. The mean age of the pooled studies was 72.1 years, while the mean baseline Clinical Dementia Rating—Sum of Boxes (CDR-SB) varied from 2.71 to 3.8. GLP-1 RAs were not associated with significant improvement in cognition (Alzheimer's Disease Assessment Scale–Cognitive Subscale: standard mean difference −0.05; 95% confidence interval [CI]: −0.12 to 0.02; <i>p</i> = 0.1928) or disease progression (CDR-SB: mean difference: 0.09; 95% CI: −0.10 to 0.28; <i>p</i> = 0.362). They were associated with a higher frequency of adverse events (RR 1.07; 95% CI: 1.04 to 1.10; <i>p</i> &lt; 0.0001) and weight loss (RR 5.01; 95% CI: 3.99 to 6.27; <i>p</i> &lt; 0.0001). Biomarker and neuroimaging findings were inconsistent and failed to translate to clinical benefit.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>GLP-1 RAs did not improve cognitive or functional outcomes in AD and were associated with adverse events. Their role may be better explored in biomarker-enriched, metabolically selected populations or assessment of GLP-1 RAs with greater brain penetrance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70334","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic intervention strategies in frontotemporal dementia: drug development pipeline","authors":"Federica Perrone,&nbsp;Nicoletta Locuratolo,&nbsp;Elena Carbone,&nbsp;Marisa Cappella,&nbsp;Roberto Rivabene,&nbsp;Elisa Fabrizi,&nbsp;Giuseppina Talarico,&nbsp;Nicola Vanacore,&nbsp;Eleonora Lacorte,&nbsp;Paola Piscopo","doi":"10.1002/trc2.70243","DOIUrl":"10.1002/trc2.70243","url":null,"abstract":"<p>Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer's disease, characterized by substantial genetic, clinical, and pathological heterogeneity. Despite progress in understanding its pathophysiology, no disease-targeted therapies (DTTs) have been approved to date. This study provides an updated overview of ongoing and completed clinical trials in FTD, analyzing therapeutic strategies, trial phases, and molecular targets. All registered trials were systematically searched on the online registers ClinicalTrials.gov, the EU Clinical Trials Register, and the International Clinical Trials Registry Platform, using the search terms “Frontotemporal Dementia,” “FTD,” and “svPPA” (semantic variant primary progressive aphasia). Included studies investigated pharmacological or cell-based interventions in Phases 1 through 4 or in trials with no reported phase. Non-pharmacological and biomarker-only trials were excluded. The Common Alzheimer's Disease Research Ontology (CADRO) was used to classify mechanisms of action. Data were collected as of February 3, 2026. A total of 49 trials were identified, investigating 35 pharmacological and three cell interventions. Among them, 16 trials (32.7%) were still active and had an expected sample size of 1036 participants. More than half of the pharmacological interventions investigated were classified as DTTs (67.3%), targeting specifically <i>GRN</i>- and <i>C9orf72</i>-associated genetic forms of FTD, while 26.5% targeted symptomatic treatments, addressing behavioral and neuropsychiatric symptoms. Seventeen molecules (32.7%) were repurposed drugs. The pipeline for the development of new potential treatments for FTD is still limited, with a predominant focus on rare genetic forms and a limited number of trials addressing sporadic FTD. Many trials remain inactive or unpublished, hindering translational progress. The scarcity of reliable biomarkers and the exclusion of patients without access to genetic testing further limits trial inclusivity. Improving biomarker research, trial transparency, and global accessibility are critical steps toward developing effective, scalable therapies for FTD.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing therapeutic approaches for agitation: A neurorelational perspective","authors":"Kathy Y. Liu,&nbsp;George Salaminios,&nbsp;Mara Mather,&nbsp;Robert Howard","doi":"10.1002/trc2.70333","DOIUrl":"10.1002/trc2.70333","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Agitation is a common, distressing, and difficult-to-treat symptom in dementia, linked to emotional dysregulation and interpersonal stress. Degenerative and compensatory changes in the locus coeruleus–noradrenergic (LC–NA) system have been implicated in agitation in Alzheimer's disease. However, substantial interindividual variability in the emergence of agitation over the course of dementia suggests that neuropathological changes alone are unlikely to fully account for individual differences in susceptibility to agitation. We explore how mentalizing capacity (the ability to understand one's own and others’ thoughts, feelings, beliefs, and intentions) in both care recipients and caregivers may influence agitation propensity. Mentalizing supports adaptive emotion regulation and may underpin person-centered care, but becomes less effective under conditions of heightened arousal and interpersonal stress. It is proposed that LC–NA regulation of arousal may influence the capacity to sustain mentalizing under stress, potentially contributing to agitation and increasing the likelihood of escalation of care. Notably, mentalizing may be compromised by different processes in care recipients and caregivers. In care recipients, neurodegeneration may impair mentalizing, potentially in part through dysregulation of the LC–NA system. In caregivers, distress, burden, and emotionally challenging interactions may undermine the capacity to maintain mentalizing. As disease progression is likely to increasingly constrain mentalizing capacity in care recipients, we consider pharmacological modulation of care recipients’ LC–NA function and psychosocial interventions to strengthen caregiver mentalizing as complementary and potentially modifiable targets for intervention. This conceptualization is best understood within a relationship-centered care perspective, which extends beyond person-centered care by emphasizing care as embedded in the dynamic relationships between caregivers and care recipients, rather than focusing solely on individual patient preferences. Taken together, these considerations inform a neurorelational framework for understanding and addressing agitation, integrating neurobiological and socio-emotional perspectives to provide a basis for personalized intervention approaches to potentially mitigate the effects of neurodegeneration on “neuropsychiatric reserve.”</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How should the results of Alzheimer's disease treatment trials be communicated to colleagues, patients, and families?","authors":"Jemma Hazan,&nbsp;Simone Salemme,&nbsp;Kathy Y. Liu,&nbsp;Robert Howard","doi":"10.1002/trc2.70330","DOIUrl":"10.1002/trc2.70330","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The approval of amyloid-lowering therapies for Alzheimer's disease (AD) has increased the importance of clearly and precisely communicating complex clinical trial findings to patients, caregivers, clinicians, and the wider public. Because the clinical relevance of the modest treatment effects observed on cognitive and functional rating scales, which served as primary trial outcome measures, is uncertain and difficult to interpret, these effects have been translated into alternative quantitative interpretations, such as relative slowing of decline and time-saved estimates, and supplemented with qualitative descriptions and patient or caregiver testimonials. In this perspective, we examine the advantages and limitations of these approaches, with a particular focus on time-saved approaches, and discuss the assumptions required to move beyond reliance on directly observed primary outcome data from clinical trials. We argue that alternative methods of communicating treatment effects may improve accessibility but introduce additional uncertainty and may lead patients and clinicians to overestimate the size of benefit because they will not appreciate some of the assumptions on which these methods are based. Clear and accurate communication of treatment benefits, risks, limitations, and evidential uncertainty is essential to support informed decision making and maintain public trust in AD research and treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frontotemporal lobar degeneration therapeutic development pipeline: 2026","authors":"Alberto Benussi,&nbsp;Aurora Saccavini,&nbsp;Federica Palacino,&nbsp;Bradley F. Boeve,&nbsp;Adam L. Boxer,&nbsp;Edward D. Huey,&nbsp;Isabelle Le Ber,&nbsp;Raffaella L. Migliaccio,&nbsp;Chiadi U. Onyike,&nbsp;Olivier Piguet,&nbsp;Yolande A. L. Pijnenburg,&nbsp;Jonathan D. Rohrer,&nbsp;James B. Rowe,&nbsp;Eino Solje,&nbsp;Markus Otto,&nbsp;Barbara Borroni,&nbsp;Jeffrey L. Cummings","doi":"10.1002/trc2.70326","DOIUrl":"https://doi.org/10.1002/trc2.70326","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Frontotemporal lobar degeneration (FTLD) comprises a group of neuropathological entities underlying a spectrum of clinical syndromes, including behavioral variant frontotemporal dementia, the primary progressive aphasias, progressive supranuclear palsy, and corticobasal syndrome. Their marked biological and clinical heterogeneity is among the reasons why no disease-modifying therapy has been approved.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We systematically mapped the 2026 therapeutic pipeline by searching ClinicalTrials.gov, the EU Clinical Trials Register, the Clinical Trials Information System, and the International Standard Randomised Controlled Trial Number (ISRCTN) registry for active interventional studies up to May 31, 2026, including Phase 1–3 pharmacological and neuromodulation trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Thirty-eight active trials were identified (19 pharmacological and 19 neuromodulation), comprising 7 Phase 1 and 11 Phase 2 studies, and 1 Phase 3 study. Neuromodulation accounted for half of the pipeline, predominantly targeting language networks in primary progressive aphasia. Disease-targeted approaches focused mainly on progranulin restoration in <i>granulin</i> (<i>GRN</i>)-FTD (frontotemporal dementia) and tau-related mechanisms. Biomarker outcomes were incorporated in 25 trials (65.8%), whereas repurposed agents represented 13.2% of interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Although the FTLD pipeline remains largely early stage, advances in mechanistically targeted therapies highlight the importance of proactive case-finding, genetically stratified trial designs, biomarker-guided diagnosis, and mechanism-based therapeutic development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical activity and combinations with modifiable factors and risk of cognitive impairment: the Whitehall II study","authors":"Yanan Zhang,&nbsp;Anwar T. Merchant,&nbsp;Chih-Hsiang Yang,&nbsp;Hanzhang Xu,&nbsp;Paul E. Schulz,&nbsp;Casey Crump,&nbsp;Jingkai Wei","doi":"10.1002/trc2.70307","DOIUrl":"https://doi.org/10.1002/trc2.70307","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Physical activity is a key modifiable protective factor for cognitive health, but randomized controlled trials initiating physical activity in late life have often failed to demonstrate significant cognitive benefits. The optimal window for prevention may be midlife, before irreversible pathology is established. We emulated a target trial to estimate counterfactual risks of cognitive impairment under hypothetical strategies of initiating or maintaining physical activity, alone or in combination with lifestyle and vascular risk modifications from midlife.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We utilized data from the Whitehall II study (<i>n</i> = 3011) with baseline ages 45 to 64, following participants from midlife for up to 18 years. We applied the parametric g-formula to handle time-varying confounding and emulate hypothetical interventions. Strategies included physical activity, alone or combined with modifications to diet, smoking, alcohol consumption, and vascular risk modification (systolic blood pressure, total cholesterol, fasting glucose, and body mass index). The primary outcome was cognitive impairment based on cognitive tests. One thousand sets of bootstrapping were conducted to obtain 95% confidence intervals (CIs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Initiating physical activity alone did not significantly reduce the 18-year cumulative incidence of cognitive impairment. However, the estimated risk of cognitive impairment was lower under the strategy combining physical activity with healthy diet and no smoking, and with normal body mass index, compared with the natural course. Also, comprehensive strategies targeting physical activity, lifestyle factors, and all vascular risk factors achieved significant risk reduction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>While physical activity initiated in midlife may be insufficient as a single intervention in this cohort, its integration into a comprehensive multidomain strategy addressing lifestyle and vascular health significantly reduces the risk of cognitive impairment. These findings support holistic prevention strategies from midlife to improve long-term cognitive outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70307","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electroencephalographic complexity and cognitive decline: Insights from approximate entropy across aging and dementia","authors":"Alessia Cacciotti,&nbsp;Anna Fabbrocino,&nbsp;Chiara Pappalettera,&nbsp;Francesca Ginatempo,&nbsp;Nicola Loi,&nbsp;Damiano Sottana,&nbsp;Franca Deriu,&nbsp;Paolo Maria Rossini,&nbsp;Fabrizio Vecchio","doi":"10.1002/trc2.70284","DOIUrl":"https://doi.org/10.1002/trc2.70284","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Physiological aging involves gradual modifications of brain activity patterns sometimes leading to pathological outcomes. Understanding changes in brain signal complexity from healthy aging to mild cognitive impairment (MCI) and Alzheimer's disease (AD) may provide insights into cognitive decline and support early diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Electroencephalography (EEG) data were collected from 269 participants divided into three groups: healthy elderly (HE, <i>n</i> = 109), MCI (<i>n </i>= 75), and AD (<i>n</i> = 85). Approximate entropy (ApEn) was computed for the total EEG spectrum and frequency bands. A random forest classifier with a one-versus-one strategy and recursive feature elimination (RFE) was used for group discrimination. Additionally, group comparisons and correlations with neuropsychological scores were performed to further investigate the functional relevance of these entropy changes by assessing their association with cognitive and functional performance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Significant group differences in total ApEn were found, particularly in central brain regions, with progressive decreases from HE to MCI and AD. Frequency-specific patterns emerged: (1) delta ApEn was increased in those with AD across the scalp; (2) alpha 1 ApEn showed frontal decreases and occipital increases in the AD group, with an intermediate pattern in MCI; (3) gamma ApEn was markedly reduced in those with AD compared to both HE and MCI groups, with central and frontal localization, and extended occipital differences in those with MCI versus AD. The classifier achieved 66.55% accuracy, with sensitivities of 78.90% (HE), 49.33% (MCI), and 65.88% (AD). Positive correlations were found between ApEn and cognitive scores in both the total EEG spectrum and gamma band; conversely, delta and alpha 1 ApEn showed negative correlations with cognitive and functional scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The distinct entropy patterns observed across frequency bands and scalp/brain regions may help characterize electrophysiological changes associated with cognitive decline and AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 4","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Humanized APP is the primary determinant of regional brain volume in humanized APOE knock-in mice: a cross-sectional ex vivo MRI study.","authors":"Avnish Bhattrai, Adam C Raikes, Roberta Diaz Brinton","doi":"10.1002/trc2.70325","DOIUrl":"10.1002/trc2.70325","url":null,"abstract":"<p><strong>Introduction: </strong>Age, Apolipoprotein ε4 (<i>APOE</i>4) genotype, and biological sex are major risk factors for late-onset Alzheimer's disease (LOAD), and preclinical mouse models enable controlled investigation of these factors. To date, humanized <i>APOE</i>4 has not recapitulated LOAD-relevant brain volume phenotypes. Given the central role of amyloid precursor protein (APP) in LOAD pathogenesis, incorporating humanized APP (<i>h</i>APP) alongside humanized <i>APOE</i> (h<i>APOE</i>) may therefore improve translational modeling of structural brain changes characterized by neuroimaging.</p><p><strong>Methods: </strong>Aged mice (mean age = 23.25 months) carrying murine (<i>m</i>) or humanized (<i>h</i>) APP and murine Apoe or h<i>APOE</i>3/3 (h<i>APOE</i>3-HOM), h<i>APOE</i>3/4 (h<i>APOE</i>4-HET), or h<i>APOE</i>4/4 (h<i>APOE</i>4-HOM) underwent in-skull ex vivo volumetric magnetic resonance imaging. Regional volumes were quantified in absolute terms and relative to total brain volume (TBV). Linear models included APP type, <i>APOE</i> genotype, and sex, with false discovery rate correction applied within contrasts.</p><p><strong>Results: </strong>Brain volumes were primarily determined by APP background, with <i>h</i>APP globally reducing total and regional volumes relative to <i>m</i>APP mice. Across <i>h</i>APP models, h<i>APOE</i>4-HOM exhibited the greatest brain-wide reductions, which was mitigated by a single h<i>APOE</i>3 allele. In contrast, mouse APP exerted modest effects in h<i>APOE</i>, with h<i>APOE</i>4 carriers exhibiting greater total volume without regional specificity. After TBV adjustment, <i>h</i>APP mice exhibited subcortical vulnerability with relative cortical preservation. Females exhibited larger brain volumes than males, independently of APP or <i>APOE</i> genotype.</p><p><strong>Discussion: </strong>h<i>APP</i> induces distinctly smaller brain volumes in this humanized <i>APOE</i> knock-in model, and h<i>APOE</i>4 homozygosity amplifies that effect, indicating genotype-dependent susceptibility. Because this study is cross-sectional and lacks histopathological confirmation, volume differences may reflect developmental or constitutive effects rather than neurodegeneration. Humanized APP and <i>APOE</i> are therefore necessary but not sufficient to recapitulate the complete volumetric signature of established LOAD. Longitudinal and histological studies are required to determine whether these differences reflect a prodromal trajectory or a developmental effect.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70325"},"PeriodicalIF":7.4,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149041898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal fluid protein elevations in Alzheimer's disease are dissociated from immune cell composition.","authors":"Sina Zaic, Theresa König, Omar Keritam, Valérie Faber, Katharina Seifried, Sara Silvaieh, Nik Krajnc, Raphael Wurm, Tandis Parvizi, Stefan Macher, Paulus Rommer, Fritz Leutmezer, Gabriel Bsteh, Elisabeth Stögmann, Thomas Berger, Tobias Zrzavy","doi":"10.1002/trc2.70321","DOIUrl":"10.1002/trc2.70321","url":null,"abstract":"<p><strong>Introduction: </strong>Elevated cerebrospinal fluid (CSF) inflammatory proteins have been reported in Alzheimer's disease (AD), yet whether they reflect peripheral immune cell infiltration or central nervous system (CNS)-intrinsic pathological processes remains unclear. We tested whether AD exhibits a distinct CSF protein signature and how it relates to CSF immune cell composition.</p><p><strong>Methods: </strong>We conducted a cross-sectional study of 64 participants: 22 with biomarker-confirmed AD (bioAD), 22 non-AD biomarker-negative cognitive controls (NAD-CC), and 20 other neurological disease controls (OND). CSF proteins were quantified using the Olink Target 96 Inflammation panel, and immune cell populations were characterized by multiparameter spectral flow cytometry. Cell-protein associations were assessed using hierarchical generalized linear models adjusted for age and sex.</p><p><strong>Results: </strong>BioAD showed widespread inflammatory and trophic protein elevation versus NAD-CC, with 21 proteins significantly increased (false discovery rate [FDR] <i>q</i> < 0.05), whereas NAD-CC was largely indistinguishable from OND. MMP-10 showed the largest effect (geometric mean ratio [GMR] = 2.10, 95% confidence interval [CI]: 1.53-2.88, <i>p</i> < 0.001). CSF immune cell populations did not differ significantly between groups; only discrete T-cell alterations were detected: reduced regulatory T cells in bioAD relative to NAD-CC (odds ratio [OR] = 0.69, 95% CI: 0.54-0.88, <i>p</i> = 0.023), but not relative to OND and minor memory subset shifts. CD8+ effector memory T cells and TNFSF14 showed the only detected AD-specific association: in bioAD, a 10-fold increase in CD8+ EM2 cells corresponded to 70% higher TNFSF14 (GMR = 1.70, 95% CI: 1.39-2.09, <i>p</i> < 0.0001).</p><p><strong>Discussion: </strong>In this feasibility-sized, cross-sectional cohort, CSF inflammatory proteins in AD appeared dissociated from immune-cell composition, potentially reflecting CNS-intrinsic processes and/or altered CSF barrier dynamics. The identified signature, including MMP-10, is hypothesis-generating and may complement conventional biomarkers for diagnosis and treatment monitoring, pending longitudinal validation.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70321"},"PeriodicalIF":7.4,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149041932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}