Transcriptomic Heterogeneity of Alzheimer's Disease Associated with Lipid Genetic Risk

Alzheimer's disease (AD) is a multifactorial disease that affects more than 5 million Americans. Multiple pathways might be involved in the AD pathogenesis. The implication of lipid genetic susceptibility on brain gene expression is yet to be investigated. The current study included 192 brain samples from AD patients who were enrolled in the ROSMAP study. The samples were genotyped and imputed to the HRC Reference Panel. Lipid polygenetic risk score was constructed from the weighted sum of genetic variants associated with low-density lipoprotein cholesterol (LDL-C). The gene expression was profiled by RNA sequencing, and the  association of gene expression with lipid polygenetic risk scores was tested by linear regression models adjusted for age, sex and APOE e4 alleles. Three genes were found to associate with lipid polygenetic risk scores, including HMCN2 (P = 3.6 × 10^-7), PDLIM5 (P = 1.2 × 10^-6), and FHL5 (P = 2.0 × 10^-6). Network analysis revealed multiple related pathways, including dopaminergic synapse (P = 4.5 × 10^-5), circadian entrainment (P = 1.1 × 10^-4), and cholinergic synapse (P = 2.3 × 10^-4). Our study underscores the importance of lipid regulation and metabolism to AD heterogeneity.