Integrative analysis of genetic variants, physical activity and brain atrophy in Alzheimer's disease

Music City Center 

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. The relationship between genetic risk factors, behavioral phenotypes and brain changes are not well understood. We use high-dimensional mediation analysis as an integrative framework to study the relationships among genetic factors, physical movement as assessed using wearable sensors, and AD-like brain atrophy quantified by radiomic features. We integrate genetic, accelerometry and neuroimaging data 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 neuro-radiomic biomarker, SPARE-AD (Spatial Pattern of Abnormality for Recognition of Early 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 to estimate potential mediating pathways between SNPs, multivariate PA signatures and SPARE-AD. Our analysis identified a total of 22 mediation pathways, indicating how genetic variants can influence SPARE-AD by altering physical activity. Our 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 disease mechanisms.