Single-Nuclei Transcriptomic Characterization of APOE4-Associated Alzheimer's Disease

Apolipoprotein E (APOE) genotype contributes significantly to Alzheimers disease (AD) risk and pathogenesis. Cell-type specific effects of APOE alleles have been studied. However, due to the variable prevalence of APOE genotypes within human populations, characterization of cell-type specific transcriptomes across APOE genotypes has been challenging. Here, we integrated previous and newly generated single-nuclei sequencing (snRNA-seq) data in the prefrontal cortex (PFC) from individuals across APOE genotypes (2/2, 2/3, 3/3, 3/4, 4/4). Clustering analysis revealed distinct excitatory and microglial subpopulations that were uniquely enriched or depleted for APOE4/4 AD. Notably, an excitatory neuronal cluster exhibited neurofibrillary tangle (NFT) signatures and was selectively depleted in APOE4/4 AD cases. In addition, several microglial subpopulations were influenced by both APOE4 dosage and disease status. Among these, the putative AD risk gene FRMD4A emerged as APOE4 dose and AD-dependent. These findings were validated by RNAscope in an extended cohort. Together, our findings provide insights into how APOE4 reshapes cellular states and contributes to cell-type-specific vulnerability in AD.