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

{"title":"The utility of a composite endpoint for tracking disease progression in Lewy body dementia.","authors":"Elie Matar, Simon R White, John-Paul Taylor, Alan Thomas, Ian McKeith, Joseph Kane, Simon Lewis, Ajenthan Surendranathan, John O'Brien","doi":"10.1002/trc2.70260","DOIUrl":"10.1002/trc2.70260","url":null,"abstract":"<p><strong>Introduction: </strong>Dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD), collectively termed Lewy body dementia (LBD), show heterogenous progression across cognitive, motor, and neuropsychiatric symptom domains, yet disease-specific endpoints are lacking. We evaluated whether a composite clinical endpoint using validated scales across different symptom domains could sensitively track disease progression and align with functional and caregiver outcomes.</p><p><strong>Methods: </strong>One hundred sixteen participants (DLB = 72; PDD = 44) were assessed at baseline, 3, and 6 months in a cluster-randomized trial comparing usual care versus management informed by an evidence-based toolkit. The Lewy Body Symptom Severity (LBSS) index was constructed by summing rescaled Mini-Mental State Examination, Movement Disorder Society Unified Parkinson's Disease Rating Scale (Part III), Dementia Cognitive Fluctuations Scale, and Neuropsychiatric Inventory 4-item subscore (including hallucinations). Linear mixed-effects models tested change over time. Validity was examined against caregiver Clinical Rating of Change (CRC), Bristol Activities of Daily Living (ADL) Scale, and caregiver Zarit Burden Interview.</p><p><strong>Results: </strong>Over 6 months, LBSS increased significantly (<i>β</i> = 0.0307; <i>P</i> = 0.0006). Simulation-based power analyses indicated greater statistical efficiency for LBSS than for any individual component. LBSS also detected a significant intervention effect (<i>P</i> = 0.0365) not observed with single-domain measures. LBSS correlated with caregiver burden (Zarit; <i>ρ</i> = 0.53, <i>P</i> < 0.001), functional dependence (Bristol ADL; <i>ρ</i> = 0.57, <i>P</i> < 0.001), and CRC (<i>ρ</i> = -0.33, <i>P</i> = 0.002), permitting derivation of a minimal clinically important difference.</p><p><strong>Discussion: </strong>A simple composite spanning cognition, parkinsonism, cognitive fluctuations, and neuropsychiatric symptoms sensitively detected short-interval progression, with improved statistical efficiency over single-domain measures, and was aligned with functional/caregiver outcomes. These findings support composite endpoints for LBD trials and can inform the design of disease-specific scales.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":"e70260"},"PeriodicalIF":7.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13239424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148201021","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":"Worth their weight in gray matter? A narrative review of cost-effectiveness analyses of monoclonal antibodies for Alzheimer's disease.","authors":"Tuyet Thao Nguyen, Bozhidar T Chakalov, Megan Van Noord, Charles DeCarli, Jeffrey S Hoch","doi":"10.1002/trc2.70267","DOIUrl":"10.1002/trc2.70267","url":null,"abstract":"<p><strong>Introduction: </strong>Monoclonal antibodies (mAbs) for Alzheimer's disease (AD) represent major therapeutic advances, but their economic value is uncertain. This review narratively examines cost-effectiveness analyses (CEAs) of aducanumab, lecanemab, and donanemab for early-onset AD.</p><p><strong>Methods: </strong>We searched Medline (via PubMed) and EMBASE in April 2026 and incremental cost-effectiveness ratio (ICER) reports for CEAs of these mAbs. Inclusion required sufficient data to calculate ICERs. Two reviewers independently screened studies, and risk of bias was assessed using Risk of Bias in Systematic Reviews. Data were synthesized narratively due to methodological heterogeneity.</p><p><strong>Results: </strong>Of 755 records screened, 16 CEAs met inclusion criteria (six aducanumab, eight lecanemab, one aducanumab/donanemab, one lecanemab/donanemab). Almost all aducanumab studies reported ICERs that exceeded commonly cited US willingness‑to‑pay thresholds (e.g., $100,000-$150,000 per quality-adjusted life year [QALY]), with ratios ranging from $127,461 to $1,581,276/QALY (2026 USD). Lecanemab results were mixed, with manufacturer‑funded models reporting ICERs below commonly cited thresholds, while other models generally exceeded them. The single donanemab analysis versus standard of care reported an ICER of $214,760/QALY (2026 USD), above commonly cited thresholds, and a Brazilian analysis comparing donanemab with lecanemab reported an ICER of $1,477,604/QALY (2026 USD). No independent study found any mAb cost savings.</p><p><strong>Discussion: </strong>ICER variability across studies, despite reliance on the same clinical trials, reflects sensitivity to assumptions and potential sponsorship bias. Evidence is limited by small numbers of CEAs, reliance on modeled rather than real-world data, and absence of formal risk-of-bias scoring for individual CEAs. The cost-effectiveness of AD mAbs in the US context remains uncertain.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":"e70267"},"PeriodicalIF":7.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148201023","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":"Single-subject proteomic signatures in Alzheimer's disease reflect clinical phenotypes and distinguish asymptomatic from symptomatic cases.","authors":"Avijit Podder, Yi Juin Liew, Gregory A Cary, Gregory W Carter, Asli Uyar","doi":"10.1002/trc2.70264","DOIUrl":"10.1002/trc2.70264","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's disease (AD) exhibits considerable inter-individual variability in clinical presentation, neuropathological burden, and underlying molecular processes. Conventional cohort-based analyses of omics molecular data often mask individual-level heterogeneity, limiting insights into precision therapeutic strategies. To address this challenge, we developed INdividual-level DIfferential GenOmics (INDIGO), a computational framework that quantifies molecular deviations for each individual relative to healthy controls, enabling subject-specific profiling of disease-associated alterations in proteomic data, with a framework that is readily applicable to other omics modalities.</p><p><strong>Methods: </strong>We applied INDIGO to dorsolateral prefrontal cortex (DLPFC) proteomic data from the Religious Orders Study and Memory and Aging Project cohort (<i>N</i> = 610). Protein-level deviations were aggregated into gene set activity scores for Kyoto Encyclopedia of Genes and Genomes pathways and curated AD Biodomain annotations. Functional alterations across AD and asymptomatic AD (AsymAD) individuals were evaluated and correlated with clinical metrics including apolipoprotein E (<i>APOE</i>) genotype, Braak stage, Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and Mini-Mental State Examination scores. Graph-based clustering was used to identify molecularly distinct subgroups based on shared patterns of functional dysregulation.</p><p><strong>Results: </strong>Limited overlap was observed between cohort-level differential expression analysis and INDIGO single-subject analyses. Individual deviations in various processes, including metabolic, immune, and epigenetic pathways, exhibited sex- and disease stage-specific patterns. Amyloid clearance and immune activation were strongly associated with <i>APOE</i> ε4 dosage, higher amyloid and tau burden, and cognitive decline, whereas upregulation of mitochondrial and synaptic modules correlated positively with preserved cognitive function. By linking individuals through concordant directional proteomic changes, we identified molecularly coherent subgroups that transcended conventional diagnostic boundaries and included both AD and AsymAD subjects. Each subgroup displayed distinct functional signatures defined by a unique set of key regulatory proteins.</p><p><strong>Discussion: </strong>These results demonstrate that single-subject omics profiling can resolve individual molecular signatures aligned with clinical and neuropathological variation in AD. By linking molecular heterogeneity with disease phenotypes, INDIGO provides a scalable framework for precision modeling and novel therapeutic target discovery.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70264"},"PeriodicalIF":7.4,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984221","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":"Reframing Alzheimer's disease as a complex adaptive system: More than an amyloid beta-tau connection.","authors":"Maurizio Giorelli","doi":"10.1002/trc2.70256","DOIUrl":"10.1002/trc2.70256","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the leading cause of dementia, but simple models focusing on amyloid beta and tau only partially explain its variability and limited success in treatment. Evidence from systems biology, neuroimmunology, connectomics, and computational modeling supports viewing AD as a complex adaptive system, a multiscale network in which genetic, molecular, cellular, vascular, and environmental factors interact in complex, non-linear ways over time. In this perspective, disease paths develop from feedback-driven instabilities that spread across different levels, while resilience and compensatory mechanisms influence individual outcomes. This new understanding has important implications: diagnostic approaches should shift from static lesion biomarkers to longitudinal, multimodal measures of network states; treatments should combine pharmacological, metabolic, vascular, inflammatory, cognitive, and neuromodulatory strategies; and adaptive, model-informed algorithms should customize the timing and dosage to each patient's unique dynamics. Recognizing the complexity enables earlier detection of critical tipping points, targeted reinforcement of resilience, and personalized intervention plans, shifting AD care from late-stage, single-target methods to precision network medicine.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70256"},"PeriodicalIF":7.4,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984188","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":"Effectiveness of Souvenaid® combined with acetylcholinesterase inhibitors on caregiver burden in Alzheimer´s disease.","authors":"José María García-Alberca, Silvia Mendoza, Paz DE LA Guía, María López DE LA Rica","doi":"10.1002/trc2.70262","DOIUrl":"10.1002/trc2.70262","url":null,"abstract":"<p><strong>Introduction: </strong>The burden experienced by caregivers of Alzheimer´s disease (AD) patients is a complex and stressful situation influenced by distinct variables, such as the patient´s need for monitoring, social isolation, mental or physical health problems, or financial challenges. In additon, behavioral and psychological symptoms of dementia are strongly associated with caregiver experiences of burden.</p><p><strong>Methods: </strong>This was a 12-month, retrospective, single-center, real-world study to evaluate the effectiveness of the combined treatment with Souvenaid and acetylcholinesterase inhibitors (AChEI) compared to treatment with either AChEI alone or Souvenaid alone on caregiver burden, anxiety and depression in patients, and AD patients attending a memory clinic. Assessments were conducted using the Zarit Burden Interview (ZBI), the Beck Depression Inventory (BDI), the State Trait Anxiety Inventory-State (STAI-S), and the Neuropsychiatric Inventory-Caregiver distress scale (NPI-D). A mixed model for repeated measures was conducted to evaluate differences from baseline to month 12 between caregivers in the three treatment groups.</p><p><strong>Results: </strong>At 12 months, caregiver burden, depression, anxiety levels, and the emotional distress in the context of behavioral and psychological symptoms of dementia (BPSD) improved in caregivers in the Souvenaid plus AChEI group (<i>n</i> = 70) compared to those in the AChEI group (<i>n</i> = 84) and those in the Souvenaid group (<i>n</i> = 66).The mean change for the ZBI score was found to be significantly higher in the Souvenaid plus AChEI group than in the AChEI group (p < 0.001) and the Souvenaid group (p < 0.001). In addition, there was a significant difference in the mean change for the BDI, STAI-S, and NPI-D scores between groups, favoring the Souvenaid plus AChEI group over the AChEI and Souvenaid groups.</p><p><strong>Discussion: </strong>In addition to assessing patients' cognitive, behavioral, and daily functioning, it is recommended regular monitoring of caregiver burden while providing support for patients with dementia. The combined treatment with Souvenaid and AChEI may have a significant impact on caregivers' experience of burden.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70262"},"PeriodicalIF":7.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13171465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147965400","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":"Vascular cognitive impairment and dementia drug-development pipeline 2025.","authors":"Ying Xu, Perminder S Sachdev, Matthew J Lennon","doi":"10.1002/trc2.70263","DOIUrl":"10.1002/trc2.70263","url":null,"abstract":"<p><strong>Introduction: </strong>There are currently no approved medicines for vascular cognitive impairment and dementia (VCID).</p><p><strong>Methods: </strong>We reviewed clinical trials across nine registries and included, summarized, and evaluated trials that had not yet published peer-reviewed results by August 22, 2025.</p><p><strong>Results: </strong>We found 88 clinical trials using 62 drugs. Cardiovascular disease-targeted therapies accounted for 37% (23 drugs). Synthetic and plant-based cognitive function enhancers accounted for 21% (13 drugs) each. Drugs targeting neuropsychiatric symptoms comprised 10% of the pipeline (six agents), biological disease-targeted therapies 5% (three agents), and other drugs 6% (four agents). There were 30 trials assessing 25 drugs in Phase 4, 24 trials assessing 21 drugs in Phase 3, 29 trials assessing 28 drugs in Phase 2, and five trials assessing four drugs in Phase 1.</p><p><strong>Discussion: </strong>While small relative to Alzheimer's disease (138 drugs, 182 trials in 2025), the drug pipeline for VCID shows some promise and will require further investment.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70263"},"PeriodicalIF":7.4,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13160922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147935416","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":"Functional connectome metrics reveal distinct prognostic subtypes in two Phase 3 gantenerumab trials.","authors":"Susanna Gobbi, Erica Silvestri, Matteo Tonietto, Gregory Klein, Martijn van den Heuvel, Stefano Magon","doi":"10.1002/trc2.70259","DOIUrl":"10.1002/trc2.70259","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's disease (AD) heterogeneity poses significant challenges for drug development, identification of individuals at risk, and treatment response prediction. Scientists have leveraged graph theory and resting-state functional magnetic resonance imaging (rs-fMRI) to successfully stratify people with AD. Still, the prognostic value of rs-fMRI graph metrics in AD clinical trials remains unclear.</p><p><strong>Methods: </strong>We analyzed rs-fMRI from participants in amyloid-lowering clinical trials. Four graph metrics-global efficiency, clustering coefficient, modularity, and shortest path length-were computed and baseline clusters defined using unsupervised k‑means. We investigated the baseline connectome of each cluster to assess the level of network dysfunction and impairment (i.e., loss of global integration, resulting in disrupted communication between brain regions and reduced global efficiency). These clusters were related to a 116-week change in cognition and brain volume using covariate-adjusted mixed-effects models.</p><p><strong>Results: </strong>Three clusters emerged with distinct functional connectome efficiency, demographic, and AD-related biomarkers profiles. These baseline differences led to significant variations in disease progression. The most impaired‑connectome cluster declined fastest, whereas the most integrated declined slowest.</p><p><strong>Discussion: </strong>rs-fMRI graph metrics might effectively stratify participants with AD in clinical trials and serve as potential prognostic biomarkers.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70259"},"PeriodicalIF":7.4,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13160931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147935377","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148066462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer's disease drug development pipeline: 2026","authors":"Jeffrey L. Cummings,&nbsp;Yadi Zhou,&nbsp;Yuxin Yang,&nbsp;Kate Zhong,&nbsp;Jorge Fonseca,&nbsp;Amanda Leisgang Osse,&nbsp;Feixiong Cheng","doi":"10.1002/trc2.70251","DOIUrl":"10.1002/trc2.70251","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Discovery and development of new therapies for Alzheimer's disease (AD) are urgently needed to address the world's growing population of individuals on the AD pathophysiological continuum. Clinicaltrials.gov is a resource for studying drugs in development for treatment of AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>There are currently 158 drugs in 192 AD trials. Of the agents in trials, 39% are small molecule disease targeting therapies (DTTs); 34% are biologic DTTs; 18% are cognition enhancing symptom targeted therapies (STTs); and 10% are STTs being developed to treat neuropsychiatric symptoms of AD. Currently active trials require 54,728 participants of which 38,417 are in Phase 3. The biopharmaceutical industry sponsors 59% of AD trials including 72% of Phase 3 trials. Repurposed drugs represent 35% of the drugs in trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The AD drug development pipeline has a growing number of trials and drugs in trials. A diverse array of AD pathophysiological processes is being addressed by drugs in trials.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846025","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148062208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}