Multivariate analysis of blood and brain transcriptome in Alzheimer’s reveals unique APOE ε4‐related immune pathways

Background While Alzheimer’s disease (AD) is generally considered a brain disease, plasma levels of AD‐related proteins including amyloid‐β, phosphorylated tau, and neurofilament light chain are associated with neurodegeneration and neuroinflammation. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier (BBB) breakdown. Method We evaluated differential expression (DE) of previously established AD genes in brains obtained from 344 pathologically confirmed AD cases and 232 controls and in blood obtained from 112 clinically diagnosed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. We analyzed DE between AD and controls in the blood and brain jointly using O’Brien’s multivariate approach in the total sample and APOE genotype groups (ε2/ε3, ε3/ε3, ε3/ε4). To identify biologically important pathways, gene set enrichment analysis was performed within APOE genotype groups using DE results for all genes ranked by Z‐score from the combined blood and brain analyses. Pathway results were corrected by the false‐discovery rate (FDR). Result Nominally significant (P