PHEWAS Approach to Study Alzheimer’s Disease

Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology. As AD develops over decades, elucidating the biological effects of AD-associated genetic variation across the adult lifespan may illuminate underlying processes in the causal pathway for AD, and potentially provide novel mid-life targets for behavioral and drug intervention.

To address this, we are utilizing high dimensional, high-quality measurements from thousands of participants in a wellness program, aged 18 to 89+, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory tests (63 standard measurements); targeted chip-based proteomics (274 proteins associated with cardiovascular disease and inflammation); and Metabolon metabolomics (753 metabolites). We have performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants previously identified in large-scale GWAS meta-analysis, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components. In secondary analyses, we have tested for SNP by sex interactions.

Study Design:

The APOE allele has emerged as the strongest genetic variant associated with Alzheimer’s disease in previous GWAS studies. In our analyses, APOE status significantly associated with cholesterol markers, multiple lipid metabolites, stress-response hormones, and levels of several proteins. All associations were observed across all age groups when stratified by decade and we identified effect modification by sex in several loci. Thus, known AD genetic variation influences lipid metabolism, immune response, and cell regulatory systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

 

Key Project Personnel:

Laura HeathNathan Price