Basic Science and Pathogenesis.

Background: Although the rate of Alzheimer's disease (AD) in African-ancestry (AA) Americans is higher than that of persons from European-ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.

Method: Utilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre-frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA-seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC. Differential gene expression was evaluated among 125 donors with a neuropathological diagnosis of AD (NIA-Reagan intermediate or high likelihood) and 82 neuropathologically confirmed controls using regression models including covariates for age at death, sex, cell-type frequencies, and RNA integrity number (RIN) calculated with Limma. FDR-corrected p-values (p) were calculated to control for the 33,611 genes examined.

Result: A total of 482 genes surpassed the multiple-testing threshold. The most significant, ADAMTS2 (p = 2.96 × 10, p = 0.001), showed increased expression in AD cases (see Table/Figure). We note that ADAMTS2 was differentially expressed in a prior EA study of neuropathologically confirmed AD cases and controls (Panitch et al. Molecular Psychiatry 2021). Additionally, a recent analysis of cognitive resilience in EA neuropathological AD cases identified a strong association with ADAMTS2 (See Li et al. AAIC2024 abstract). Of the differentially expressed genes observed in the Panitch et al. EA study, 385 (35%) were nominally significant,65 (5.8%) were corrected significant, and most (89%) of these genes had the same effect direction in the AA cohort. Some of the observed associations appear to be AA specific (e.g., EFR3B, IRS4, and CA12; see Table). Additionally, we found nominally significant (p<0.05) associations with expression of APOE (Log2 fold change [L2FC = -0.20, p = 0.012) and several other established AD genes including SORL1 (L2FC = -0.10, p = 0.014) and IGF1R(L2FC = 0.11, p = 0.0013).

Conclusion: This largest-ever (to our knowledge) gene expression study of AD in postmortem brain tissue from AA donors implicates many more genes as having a role in AD in this population than previously identified in genome-wide association studies and provides insight into trans-ancestry differences risk for AD.