Alzheimer's & Dementia最新文献

Introduction: Sleep disturbances are common and distressing for people with dementia and their family caregivers, with limited treatment options. The DREAMS START (Dementia RElAted Manual for Sleep; STrAtegies for RelaTives) multi-component intervention for sleep disturbance in people at home with dementia is clinically and cost-effective at 8 months. In this long-term follow-on study, we assessed 2-year clinical effectiveness.

Methods: We recruited dyads of people with dementia and their family caregivers from community settings, for a two-arm, multi-center, single-blind, parallel-arm, superiority trial with the primary outcome Sleep Disorders Inventory (SDI). Analyses were intention to treat.

Results: We randomized 377 dyads, 189 to treatment-as-usual (TAU) and 188 to intervention; 177 dyads (46.9%) were followed up at 24 months. Two-year adjusted mean SDI score was lower in the intervention arm than TAU (-5.40; 95% CI -9.14 to -1·67; p = 0·005).

Discussion: In this follow-on study we demonstrate 2-year improvement in sleep disruption for people with dementia. DREAMS START has potential for delivery at scale.

Chronic diseases, including Alzheimer's disease (AD) and related dementia (ADRD), do not exist solely as isolated entities. Instead, they weave concomitant trajectories of multiple diseases, conditions, behaviors, and risks, mutually influencing each other's course and natural history, in ways yet unexplored. Electronic health records (EHRs) provide us with a unique opportunity to look at related and unrelated clinical trajectories over time, thus potentially providing insight into unrecognized prodromes, while incorporating the complexities of patients' lives. We harmonize and federate a three-city EHR metaplatform of nearly 10 million patients (∼60,000 with AD/ADRD), which we further embed within census tracts, to contextualize these health trajectories. Our multidisciplinary approach ambitions a unique dynamic platform to inform strategies to tailor risk prediction, complex clinical management, and real-world evaluation of future treatments of AD/ADRD. We present the rationale for and design of the Multimorbidity Three-City Alzheimer's Disease EHR (M3AD) Study and real-world data metaplatform, progress and demonstration of feasibility, its expected singular and complementary contributions to the field. HIGHLIGHTS: Our success in living longer lives often brings chronic conditions and multimorbidity. Alzheimer's research should comprise life trajectories' complexity in multimorbidity. New real-world analytical approaches allow integrated prediction of Alzheimer's disease. We are building a three-city electronic health record (EHR) metaplatform for prediction, prevention, and impact We further embed EHR within census tracts to contextualize Alzheimer's trajectories.

Introduction: Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-beta (Aβ) plaques, tau tangles, and neurodegeneration (ATN framework). While neuroimaging detects these changes, it is costly and not widely accessible. Blood-based biomarkers offer scalable alternatives for early detection.

Methods: We integrated plasma biomarkers, neuroimaging, and cognitive data from two large cohorts. We examined multivariate patterns of plasma Aβ42/Aβ40, phosphorylated tau (p-tau) 217, p-tau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) that predict amyloid, tau, neurodegeneration, and memory decline.

Results: Specific plasma biomarker combinations predicted amyloid burden in the precuneus, tau in the entorhinal cortex, hippocampal atrophy, and memory decline. Models trained in one cohort accurately predicted outcomes in the other, confirming cross-cohort generalizability.

Discussion: Distinct plasma signatures reflect underlying AD pathways, supporting the use of blood-based biomarkers as cost-effective, noninvasive tools for early detection, disease monitoring, and individualized risk profiling.

Introduction: Early detection of neuroanatomical changes in preclinical Alzheimer's disease (AD) is critical for timely intervention. However, conventional magnetic resonance imaging (MRI) and fluid biomarkers often lack sensitivity to subtle structural alterations in early disease stages.

Methods: To identify early brain alterations, we applied a perturbation-based brain similarity approach to cognitively normal participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies (OASIS), stratified by amyloid status. We evaluated its predictive performance for cognition and diagnostic conversion against cortical thickness, volumetric MRI, and fluid biomarkers.

Results: In both cohorts, brain similarity consistently outperformed other biomarkers across cognitive domains and amyloid groups. It also achieved superior accuracy in predicting clinical conversion and exhibited associations with cytoarchitectural organization.

Discussion: These findings highlight brain similarity as a sensitive marker of early neuroanatomical disruption in AD. Its ability to detect subtle structural changes before overt atrophy underscores its potential for early disease monitoring and treatment assessment in preclinical AD trials.

Highlights: Brain similarity captures early brain changes in preclinical Alzheimer's disease (AD). Brain similarity outperforms conventional biomarkers such as cortical thickness, volume measures, and fluid biomarkers in predicting cognitive decline. Brain similarity predicts conversion to mild cognitive impairment and AD more accurately than traditional imaging markers, and its predictive performance is further improved when combined with fluid biomarkers. Brain similarity captures structural disruptions associated with cortical layer II of the cytoarchitectonic lamina of human neocortex.

Introduction: The infectious hypothesis suggests that microbes like herpesviruses may play a role in the pathogenesis of Alzheimer's disease (AD) and other related dementias through methods that may include viral genome integration. The occurrence of herpesvirus genome integration in dementia patients has not been thoroughly characterized.

Methods: Over 7500 total whole-genome sequences from control, frontotemporal dementia/amyotrophic lateral sclerosis spectrum, Lewy body dementia (LBD), multiple system atrophy (MSA), and AD cohorts were screened for the integration of pathogen genomes using the PathSeq computational tool.

Results: Low PathSeq scores for human herpesvirus 6 (HHV-6) were consistent with the suspected integration of viral genome segments. The LBD and MSA cohorts had a significantly higher prevalence of this partial HHV-6 genome integration.

Discussion: This higher prevalence in both synucleinopathies was not noted in other herpesviruses, suggesting that the integration of HHV-6 may play a role in a subset of these patients.

Highlights: Over 7500 whole-genome sequences from controls and dementia patients were analyzed. Sequences consistent with integrated herpesviruses were identified using PathSeq. Prevalence of partial HHV-6 integration was higher in synucleinopathies. Herpesviruses genome integration may play a role in subsets of dementia patients.

Introduction: Dysregulation of the peripheral immune system may increase Alzheimer's disease (AD) risk, but the underlying cell type-specific mechanisms remain unclear.

Methods: We conducted Mendelian randomization and colocalization analyses of 4489 genes using single-cell expression quantitative trait locus data from unstimulated and stimulated peripheral immune cells, integrated with an AD genome-wide association study (N = 455,258). Spatial transcriptomics of brain tissue samples was used to identify brain-infiltrating immune cells.

Results: Thirteen genes were associated with AD risk. Expression of BIN1, CTSW, CTSH, HLA-DRB1, TSTD1, PLEKHA1, and SCIMP increased AD risk, while EPHA1-AS1, FCER1G, FIBP, KAT8, STX4, and HLA-DQA1 reduced it. These associations were peripheral immune cell type and state specific. PLEKHA1 and TSTD1 were upregulated and FIBP downregulated in natural killer and T cells in AD brain tissue.

Discussion: These findings link immune cell-specific gene expression to AD risk across activation states and within brain-infiltrating immune cells, highlighting potential targets for immune-based AD prevention and treatment.

Introduction: The alterations of free water (FW) in behavioral variant frontotemporal dementia (bvFTD) and its clinical correlations remain unclear.

Methods: FW levels in the whole brain and specific white matter fiber tract was evaluated in 112 bvFTD patients and 103 normal controls.

Results: BvFTD patients exhibited elevated FW in the whole brain and regional white matter tracts, especially in the uncinate fasciculus and cingulum hippocampus. FW was correlated with perivascular spaces (PVSs) and diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index. FW was also correlated with clinical scales, gray matter volume, and glucose metabolism. Additionally, FW was correlated with plasma glial fibrillary acidic protein and total tau. Mediation analyses showed that FW mediated the association between PVS and ALPS, and brain neurodegeneration mediated the association between FW and clinical scores.

Discussion: Elevated FW is involved in bvFTD and contributes to glymphatic dysfunction and neurodegeneration.