Identifying context‐specific genetic variants and molecular pathways associated with resilience to Alzheimer’s disease in the induced immune response

Neurodegenerative pathologies consistent with Alzheimer’s disease (AD) are common in older adults even among those without cognitive symptoms. Genome‐wide association studies (GWAS) have identified loci associated with better‐than‐predicted cognitive performance for a given level of neuropathology, described as resilience to AD symptoms. Transcriptome‐wide association studies (TWAS) provide powerful mechanistic insights bridging the association between loci and phenotype by implicating genes. We hypothesize that genetic variants influence resilience phenotypes by altering the function and response of monocytes, one of the premier immune cells involved in neuroinflammation. Moving to test this hypothesis, we have developed monocyte TWAS reference panels based on expression from a naïve state and following in vitro stimulations which can reveal important associations only seen in an inflammatory context.