Blood co‐expression network analysis identifies molecular pathways involved in cognitive resilience

Abstract

AbstractBackgroundTwo major risk factors of Alzheimer’s disease (AD) are advanced age and the APOE‐ε4 risk allele. However, despite having these risk factors, some individuals escape from developing AD or have slower cognitive decline. In this study we hypothesized that “resilient” individuals, defined as those who remain cognitively normal despite being >80 years‐old and carrying at least one copy of the APOE‐ε4 allele, have concerted changes in their blood transcriptomes that are associated with resilience to AD.MethodWe generated blood RNA‐sequence data from 105 APOE‐ε4 carriers from the Mayo Clinic Study of Aging (MCSA) who remained cognitively normal after age 80 (resilient), or who developed mild cognitive impairment (MCI) or AD (non‐resilient). Weighted gene co‐expression network analysis (WGCNA) was performed to evaluate the association of the blood co‐expression network with primary phenotypes of resilience and memory scores. To validate our findings, we constructed a consensus co‐expression network using both MCSA and a replication cohort of blood microarray data from 91 Alzheimer’s Disease Neuroimaging Initiative (ADNI) study participants who had a similar demographic profile. We annotated the consensus modules for their enrichment of cell types, biological processes, genes within previously published genome‐wide significant (GWS) AD‐associated loci, and genes that reside in consensus modules built from seven brain regions across three different autopsy cohorts. To identify genetic variants regulating blood consensus module co‐expression, we performed module quantitative trait locus (modQTL) analysis.ResultWe found co‐expression modules significantly (q<0.05) correlated with the memory phenotype, logical memory delayed recall, across both MCSA and ADNI cohorts. Some of these modules were enriched with blood cell types and biological processes, including telomere maintenance, mitochondrial functions, and immune response. We found 1 module significantly (q<0.05) enriched with genes near GWS AD‐associated loci and 4 modules with genes in brain consensus modules. Lastly, we found 8 modQTLs significantly (Bonferroni‐p<0.05) associated with the co‐expression of 5 different modules.ConclusionWe identified blood co‐expression modules, biological pathways and specific genetic variants associated with cognitive resilience in the presence of AD risk factors. This study provides novel insights into the potential role of peripheral blood in the development of and resilience to AD.