Alzheimer s & Dementia, Год журнала: 2024, Номер unknown
Опубликована: Дек. 31, 2024
White matter hyperintensity volumes (WMHVs) are disproportionally prevalent in individuals with Alzheimer's disease (AD), potentially reflecting neurovascular injury. We quantify the association between AD polygenic risk score (AD-PRS) and WMHV, exploring single-nucleotide polymorphisms (SNPs) that proximal to genes overexpressed cerebrovascular cell species.
Язык: Английский
Alzheimer s & Dementia, Год журнала: 2024, Номер 20(9), С. 6146 - 6160
Опубликована: Июль 29, 2024
Abstract INTRODUCTION Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, a key step toward precision medicine. METHODS We computed pathway‐specific scores (GRSs) in non‐demented individuals investigated AD variants predict cerebrospinal fluid (CSF) imaging biomarkers reflecting pathology, cardiovascular, white matter integrity, brain connectivity. RESULTS CSF amyloidbeta phosphorylated tau were most GRSs. Inflammatory pathways associated with cerebrovascular disease, whereas quantitative measures of lesion microstructure integrity predicted by clearance migration pathways. Functional connectivity alterations involved signal transduction synaptic communication. DISCUSSION This study reveals distinct profiles association pathophysiological aspects predementia stages AD, unraveling the substrates heterogeneity AD‐associated endophenotypes promoting forward understanding development personalized therapies. Highlights Polygenic for encompasses six that can be quantified scores, differentially relate biomarkers. are mostly burden. White health membrane functional communication
Язык: Английский
Процитировано
5
Alzheimer s & Dementia, Год журнала: 2025, Номер unknown
Опубликована: Янв. 27, 2025
Abstract INTRODUCTION Traditional multivariate methods for neuroimaging studies overlook the interdependent relationship between brain features. This study addresses this gap by analyzing relative volumetric patterns to capture how Alzheimer's disease (AD) and genetics influence structure along continuum. METHODS analyzed data from participants across AD continuum Families (ALFA) Disease Neuroimaging Initiative (ADNI) studies. Compositional analysis (CoDA) was exploited examine variations that (1) were linked different stages compared cognitively unimpaired amyloid‐β–negative (CU A−) individuals (2) varied genetic risk. RESULTS stage–specific compositional scores identified, differentiating CU A− those in more advanced stages. Genetic risk–stratified models revealed a broader landscape affecting morphology AD, beyond well‐known apolipoprotein E ε4 allele. DISCUSSION CoDA emerges as an alternative framework deepen understanding of AD‐related structural changes support targeted interventions at higher Highlights variation region volumes, captured scores, capable discerning subjects within other disease‐stage groups also uncovered vulnerability specific regions each stage is integrating magnetic resonance imaging two cohorts without stringent requirements harmonization. translates advantage, traditional methods, strengthens reliability cross‐study comparisons standardizing despite labeling agreements, facilitating collaborative large‐scale research. The algorithm sensitive AD‐specific effects, main display little overlap with age‐specific score. provides accurate addressing its nature, which can development approaches, opening new avenues enhancing health.
Язык: Английский
Процитировано
0
Brain and Behavior, Год журнала: 2025, Номер 15(2)
Опубликована: Фев. 1, 2025
ABSTRACT Background Alzheimer's disease (AD) and white‐matter structural connectivity have been linked in some observational studies, although it is unknown if this a causal relationship. The purpose of study was to examine the impact various on AD via two‐sample multivariate Mendelian randomization (MR) approach. Methods genome‐wide association (GWAS) Wainberg et al. provided summary data connectivity, Bellenguez al.’s GWAS aggregated for AD. MR methods included inverse variance weighted, Egger, simple mode, weighted median, mode. Heterogeneity, horizontal pleiotropy, “leave‐one‐out” analysis guaranteed robustness causation. Finally, reverse conducted that showed positive results forward analysis. Results Among 206 connections, we identified 10 connections were strongly correlated with genetic susceptibility Right‐hemisphere limbic network thalamus salience_ventral attention accumbens positively likelihood AD, while remaining 8 negatively related None above relationship Conclusion Our reveals certain degree between which may provide support future diagnosis treatment
Язык: Английский
Процитировано
0
Brain, Год журнала: 2024, Номер 147(8), С. 2680 - 2690
Опубликована: Май 30, 2024
Abstract Alzheimer’s disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression biomarkers has condensed into ATN framework, each can be either positive (+) or negative (−). Over past decades, genome-wide association studies implicated ∼90 different loci involved with development late-onset disease. Here, we investigate whether genetic risk for contributes equally to stages it exhibits a stage-dependent effect. Amyloid (A) status was using combination available PET CSF Disease Neuroimaging Initiative cohort. In 312 participants biomarker-confirmed A−T− status, used Cox proportional hazards models estimate contribution APOE polygenic scores (beyond APOE) convert A+T− (65 conversions). Furthermore, repeated analysis 290 investigated conversion A+T+ (45 Both survival analyses were adjusted age, sex years education. For from A+T−, APOE-e4 burden showed significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70–4.89; P < 0.001], whereas did not (HR 1.09; CI: 0.84–1.42; 0.53). Conversely, transition A+T+, reduced 1.62; 1.05–2.51; 0.031), an increased 1.73; 1.27–2.36; 0.001). The marginal driven e4 homozygotes 2.58; 1.05–6.35; 0.039) as opposed heterozygotes 1.74; 0.87–3.49; 0.12). unfolds fashion. A better understanding interplay between stage lead more mechanistic molecular processes leading disease, addition opening therapeutic windows targeted interventions.
Язык: Английский
Процитировано
3
Alzheimer s & Dementia, Год журнала: 2024, Номер unknown
Опубликована: Дек. 31, 2024
White matter hyperintensity volumes (WMHVs) are disproportionally prevalent in individuals with Alzheimer's disease (AD), potentially reflecting neurovascular injury. We quantify the association between AD polygenic risk score (AD-PRS) and WMHV, exploring single-nucleotide polymorphisms (SNPs) that proximal to genes overexpressed cerebrovascular cell species.
Язык: Английский
Процитировано
0