Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) epsilon 4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE epsilon 4, we examined the dorsolateral frontal cortex from deceased participants within a community-based aging cohort (n=154). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology only in APOE epsilon 4 positive participants (p=0.001). The cytokines IL-10, IL-13, IL-4, and IL-1 alpha were negatively associated with tau pathology, independent of A beta(1-42) levels, only in APOE epsilon 4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE epsilon 4 negative participants. These associations are largely absent in the presence of APOE epsilon 4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE epsilon 4 mediates an altered inflammatory response and increased tau pathology independent of A beta(1-42) pathology.