Abstract

Alzheimer’s disease (AD) is a debilitating brain disorder with staggering human and financial costs. While genomic studies increasingly identify genetic risk alleles that correlate with AD, there is still no clear picture of the underlying molecular and cellular mechanisms involved. My lab uses a multi-pronged approach to delineating how cellular, molecular and brain circuit dysfunctions contribute to AD. We recently reported the first single-nucleus transcriptomic analysis of the prefrontal cortex to accurately map the cell types and molecular pathways impacted by AD. Apolipoprotein E4 (ApoE4) is the strongest known genetic risk variant for sporadic Alzheimer’s disease (AD), but a comprehensive understanding of the cell-type-specific effects of APOE4 in the human brain in the presence and absence of AD pathology has yet to be achieved. Our recent analysis of single nucleus transcriptomics from a sex-balanced cohort of individuals comprised of APOE3 and E4 carriers indicated that cell-type-specific ApoE effects can arise in non-ApoE-expressing cell types. We also identified multiple processes that are perturbed in AD pathology exclusively in the context of ApoE4. In parallel, we conducted lipidomic analyses in ApoE4-iPSC-induced astrocytes derived from human ApoE4 carriers. These results revealed that ApoE4 causes widespread changes in lipid homeostasis that result in increased unsaturation of fatty acids and an accumulation of neutral lipids in lipid droplets in astrocytes. In addition, ApoE4 oligodendrocytes exhibit increased cholesterol pathway activity and decreased myelination gene expression. Taken together, our collected body of work illustrates how ApoE4 causes widespread molecular and cellular alterations in multiple cell types to facilitate the development of AD phenotypes.