Transcript Levels in Plasma Contribute Substantial Predictive Value as Potential Alzheimer's Disease Biomarkers in African Americans

Abstract

Background: African Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. Method: Utilizing FCA 3 DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. Findings: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. ROC analysis of age, sex APOE-e4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% AUC to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-e4 dosage. Interpretation: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. Funding: National Institute on Aging, Florida Health Ed and Ethel Moore Alzheimer’s Disease grants. Declaration of Interest: None to declare. Ethical Approval: Informed consent and approval by the Mayo Clinic Institutional Review Board was obtained.