Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) presents complex molecular heterogeneity, influenced by a variety of factors including heterogeneous phenotypic, genetic, and neuropathologic presentations. Regulation of gene expression mechanisms is a primary interest of investigations aiming to uncover the underlying disease mechanisms and progression.

Method: We generated bulk RNA-sequencing in prefrontal cortex from 565 AD brain samples (non-Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks, and conducted differential gene expression and enrichment analyses. We sought to identify cross-ancestry and ancestry-specific differentially expressed genes (DEG) and pathways across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We validated our findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095). Lastly, we validated top DEG using publically-available human single-nucleus RNA sequencing (snRNAseq) data.

Result: AD-known genes VGF (LFC = -0.661, p = 3.78) and ADAMTS2 (p = 1.21) were consistently differentially expressed across statistical models, ethnic groups, and replicated in ROS/MAP (Figure 1). Genes from the heat shock protein (HSP) family, e.g. HSPB7 (p = 3.78), were the top DEG, also replicated in ROS/MAP. Ethnic-stratified analyses prioritized TNFSF14 and SPOCD1 as top DEG in Hispanic samples. Gene set enrichment analysis highlighted several significantly pathways, including "TYROBP causal network in microglia" (WP3945; p = 1.68) and "Alzheimer Disease" (WP5124; p = 4.24). snRNAseq validated several DEG, including VGF downregulated in neurons (p = 1.1).

Conclusion: To our knowledge, this is the largest diverse transcriptome study for AD in post-mortem tissue. We identified perturbated genes and pathways resulting in cross-ethnic and ethnic-specific findings, ultimately highlighting the importance of diversity in AD investigations.