Journal Article

High-dimensional mediation analysis reveals the mediating role of physical activity patterns in genetic pathways leading to AD-like brain atrophy

Davatzikos, Christos, Mu, Shizhuo, Bao, Jingxuan, Shen, Li, Xu, Hanxiang, Shou, Haochang

2025

Overview

Background Alzheimer’s disease (AD) is a complex disorder that affects multiple biological systems including cognition, behavior and physical health. Unfortunately, the pathogenic mechanisms behind AD are not yet clear and the treatment options are still limited. Despite the increasing number of studies examining the pairwise relationships between genetic factors, physical activity (PA), and AD, few have successfully integrated all three domains of data, which may help reveal mechanisms and impact of these genomic and phenomic factors on AD. We use high-dimensional mediation analysis as an integrative framework to study the relationships among genetic factors, PA and AD-like brain atrophy quantified by spatial patterns of brain atrophy. Results We integrate data from genetics, PA and neuroimaging measures collected from 13,425 UK Biobank samples to unveil the complex relationship among genetic risk factors, behavior and brain signatures in the contexts of aging and AD. Specifically, we used a composite imaging marker, Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD) that characterizes AD-like brain atrophy, as an outcome variable to represent AD risk. Through GWAS, we identified single nucleotide polymorphisms (SNPs) that are significantly associated with SPARE-AD as exposure variables. We employed conventional summary statistics and functional principal component analysis to extract patterns of PA as mediators. After constructing these variables, we utilized a high-dimensional mediation analysis method, Bayesian Mediation Analysis (BAMA), to estimate potential mediating pathways between SNPs, multivariate PA signatures and SPARE-AD. BAMA incorporates Bayesian continuous shrinkage prior to select the active mediators from a large pool of candidates. We identified a total of 22 mediation pathways, indicating how genetic variants can influence SPARE-AD by altering physical activity. By comparing the results with those obtained using univariate mediation analysis, we demonstrate the advantages of high-dimensional mediation analysis methods over univariate mediation analysis. Conclusion Through integrative analysis of multi-omics data, we identified several mediation pathways of physical activity between genetic factors and SPARE-AD. These findings contribute to a better understanding of the pathogenic mechanisms of AD. Moreover, our research demonstrates the potential of the high-dimensional mediation analysis method in revealing the mechanisms of disease.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Activity patterns / Advertising executives / Aging / Algorithms / Alzheimer's disease / Atrophy / Bayesian analysis / Biobanks / Bioinformatics / Biomarkers / Biomedical and Life Sciences / Brain / Brain research / Cognition / Computational Biology/Bioinformatics / Computer Appl. in Life Sciences / Data compression / Data Mining and Knowledge Discovery / Dimensional analysis / Disease / Disease mechanism / Exercise / Genetic diversity / Genetic factors / Genetic risk factors / Genetic variance / Genetics / Health risk assessment / High-dimensional mediation analysis / Integrative Analysis of Multi-Omics Data for Precision Medicine / Life Sciences / Machine learning / Magnetic resonance imaging / Mediation / Medical imaging / Neurodegenerative diseases / Neuroimaging / Nucleotides / Physical activity / Physical fitness / Principal components analysis / Public health / Risk factors / Risk taking / Signatures / Single nucleotide polymorphisms / Single-nucleotide polymorphism / SPARE-AD index / Statistical analysis / Variables