Alzheimer's & Dementia最新文献

Ethnic disparities in cerebral small vessel disease (CSVD) have been reported, but no systematic synthesis has compared markers and vascular risk factors across populations. We conducted a PROSPERO-registered systematic review and meta-analysis (CRD42024518105) including over two million community-dwelling adults. A two-tier ethnicity framework was applied. Tier 1 used broad US Office of Management and Budget-aligned categories to maximize comparability, showing that Asians with higher cerebral microbleeds, Whites with greater metabolic risks, Blacks with higher hypertension, and Hispanics with elevated diabetes. Tier 2 enabled finer intra-Asian subgrouping, revealing Chinese cohorts with greater white matter hyperintensity (WMH) and hemorrhagic burden, Japanese with a lacunar-predominant profile but lower microbleeds, and Koreans with blood pressure-linked WMH. Ethnicity also moderated key risk-lesion associations, including stronger effects of diabetes on WMH and lacunes in Chinese and of systolic blood pressure on WMHs in Koreans. These findings highlight that CSVD phenotypes differ across populations, reflecting complex interactions between vascular, genetic, and environmental factors. HIGHLIGHTS: First meta-analysis of CSVD markers stratified by global ethnic groups. Tier 1: Asians had higher CMBs and lacunes; Whites had higher metabolic risk. Tier 2: Chinese showed higher WMHs and CMBs; Japanese had more lacunes, fewer CMBs. Risk-CSVD associations varied by ethnicity, including diabetes and blood pressure. Results suggest need for ethnicity-informed prevention and harmonised reporting.

Introduction: Alzheimer's disease (AD) involves complex regulatory disruptions across multiple brain cell types, yet the comprehensive intracellular causal mechanisms remain poorly understood.

Methods: We present an integrative analysis framework using single-nucleus transcriptomics with matched subject-level genotype data from 272 AD patients in the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and construct causality-based, cell-type-specific gene regulatory networks (GRNs).

Results: Our method identifies regulatory genes among transcription factors (TFs) and non-TFs, generating a complete and accurate causal regulatory map across brain cell types. Our analyses reveal both established and novel regulations, pathways, and cell-type-specific hub genes in AD. Beyond constructing transcriptome-wide GRNs, we quantitatively evaluate hub genes and distinguish those with regulatory versus responsive roles.

Discussion: Our study provides a comprehensive map of cell-type-specific causal GRNs in AD, with a methodology applicable to other complex diseases such as cancer, enabling dynamic pathway exploration, hypothesis generation, and functional interpretation.

Highlights: Comprehensive causal regulatory maps across six brain cell types revealed cell-type-specific regulatory mechanisms that move beyond traditional correlation-based and TF-centric model limitations. Novel and established hub genes and functional modules were compared across cell types, providing insights into cellular functions related to AD. Hub gene roles as regulators or targets were quantitatively evaluated within cell-type GRNs. The constructed GRNs show upstream non-TF genes regulating TFs and interconnected TF regulatory modules, highlighting the complexity of AD regulatory mechanisms beyond TF-centric assumptions.

Introduction: Neuritin-1 (NRN1) was identified as a synaptic protein associated with cognitive resilience to Alzheimer's disease (AD).

Methods: Target risk score and cell type expression profiles were generated for NRN1 using methods developed by the Emory-Sage-SGC-JAX Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Center and Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD). Antibody characterization was conducted using Western blots and densitometry to assess the relative protein abundances of NRN1 in rodents, humans, and cell models.

Results: NRN1 has a TREAT-AD target risk score of 3.29 out of 5. Based on single-nucleus RNA sequencing from SEA-AD, NRN1 expression in excitatory neurons tends to decrease with increasing donor pseudo-progression. Abcam ab64186 polyclonal NRN1 antibody detects NRN1 protein in vitro and in vivo at molecular weights that suggest NRN1 forms a homodimer. NRN1 protein abundance is comparable among controls and primary tauopathy cases, as well as Tau P301S mice and non-transgenic littermates at 3 and 9 months.

Discussion: These findings advance the investigation of NRN1 as a therapeutic candidate for AD.

Introduction: The locus coeruleus (LC) is an early site of Alzheimer's disease (AD) pathology, yet the role of brainstem astrocytes in early, sex-dependent vulnerability remains unclear.

Methods: In 2- to 3-month-old APP/PS1 mice, we combined in vivo proton magnetic resonance spectroscopy (MRS) of the brainstem with region-resolved molecular analyses, including quantitative real-time polymerase chain reaction, amyloid beta 42 (Aβ42) oligomers enzyme-linked immunosorbent assay, lactate assay, immunohistochemistry, immunoblotting, astrocyte isolation, and 3D structural assessment. Environmental enrichment (EE) served as a non-pharmacologic intervention.

Results: Females exhibited higher brainstem Aβ42 oligomers and an astrocyte-weighted MRS profile. Pontine glial fibrillary acidic protein (GFAP), complement component 3, and nuclear factor kappa-light-chain-enhancer of activated B cells were selectively upregulated without pan-reactive astrocytic and microglial markers. LC-restricted GFAP elevation occurred without changes in astrocyte counts or morphology, indicating a "primed" state. Females also showed higher lactate levels, increased monocarboxylate transporter 2 expression, and elevations in selected oxidative phosphorylation-associated transcripts, and reduced astrocytic alpha 2A-adrenergic receptor expression. EE normalized noradrenergic and pontine astrocytic changes.

Discussion: Female-biased, LC-centric astrocytic priming emerges early in this amyloid-driven model and is modifiable.

Introduction: In preclinical Alzheimer's disease (AD), amyloid accumulates in the brain while individuals remain cognitively unimpaired (Clinical Dementia Rating^® [CDR] = 0). Differentiating trajectories of healthy aging and preclinical AD is challenging as both are associated with age-related impairments (e.g., falls).

Methods: Longitudinal cohort study. We monitored falls for 1 year among 125 CDR 0 older adults and assessed preclinical AD status (amyloid). We continued to evaluate CDR annually (median 10 years). The cohort was grouped: Preclinical AD-Fall-, Preclinical AD-Fall+, Preclinical AD+Fall-, and Preclinical AD+Fall+. Survival analysis examined time to progression to CDR 1 (mild dementia) by group.

Results: Participants were 74 years (mean) at baseline, 62% female, 96% White. Preclinical AD+Fall+ progressed to CDR 1 most rapidly. Preclinical AD-Fall- progressed least quickly. Preclinical AD+Fall- and Preclinical AD-Fall+ had similar progression rates.

Discussion: Falls may associate with faster progression of AD dementia, potentially reflecting motor and gait dysfunction intrinsic to disease progression.

Introduction: Automated cerebrospinal fluid (CSF) biomarker assays have largely replaced manual immunoassays for measuring amyloid pathology in CSF. We refitted and validated the ABIDE model, predicting progression from mild cognitive impairment (MCI) to dementia, with CSF measurements from the automated Elecsys platform.

Methods: We included 2413 MCI participants (998 [41%] amyloid-positive) from seven observational cohorts. Elecsys was used in 958 (40%) participants. The parameters of the previous ABIDE Cox model were re-estimated. Model discrimination and calibration were evaluated with leave-one-cohort-out cross-validation.

Results: During follow-up, 1034 (42%; 585 [58%] amyloid-positive) participants developed dementia. Discrimination was good with Harrell's C of 0.70 (95% confidence interval [CI]: 0.66-0.73). Calibration was good in the total population and amyloid-positive subgroup, with substantial predicted progression risks for all amyloid-positive participants.

Discussion: We refitted the ABIDE model, predicting MCI to dementia progression, with automated CSF measurements. The model was well calibrated in amyloid-positive patients and may support clinical discussions regarding ATTs.

Introduction: This paper presents the development of a framework to assess the use and experiences of non-pharmacological interventions (NPIs) supporting sleep, including technological and indoor environmental quality (IEQ) measures. Sleep disturbances are common in people with dementia (PwD) and increase caregiver burden. Pharmacological treatments pose risks, highlighting the need for effective NPIs.

Methods: The framework was designed through literature review and expert consensus, and piloted over three weeks with two community-dwelling PwD and one caregiver.

Results: Findings were analyzed to improve the framework on explanation of NPIs, questionnaires, and sleep monitoring. The framework integrates methods to assess user experiences and to monitor sleep and IEQ parameters, due to their impact on sleep.

Discussion: The final framework, DESMEE-CAP, has demonstrated validity and utility in capturing experiences without disrupting routines. While promising, the small sample size limits generalizability.

Highlights: Development of a framework, in co-creation, that supports research on the use of non-pharmacological interventions (NPIs) for sleep support for community-living people with dementia and their caregivers. Attention to sleep quality and appropriate support is needed, and insights are provided through the use of the developed framework. Contribution to the development of appropriate, non-pharmacological support for sleep of people with dementia and their caregivers at home.