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

Abstract

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) ε4 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 ε4, 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 ε4 positive participants (p = 0.001). The cytokines IL-10, IL-13, IL-4, and IL-1α were negatively associated with tau pathology, independent of Aβ 1-42 levels, only in APOE ε4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE ε4 negative participants. These associations are largely absent in the presence of APOE ε4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE ε4 mediates an altered inflammatory response and increased tau pathology independent of Aβ 1-42 pathology.Alzheimer's disease (AD), the leading cause of dementia, is a progressive neurodegenerative disorder with both genetic and environmental risk factors. Many of the genes associated with AD have small effects and are associated with immunological and inflammatory pathways in the brain 1,2 . In contrast, the apolipoprotein E (APOE) ε4 allele is associated with a dramatic increase in the risk of developing AD and a younger age of symptom onset 3,4 . APOE may contribute to the development of AD through a variety of mechanisms, including increased beta-amyloid (Aβ) levels as well as an altered neuroinflammatory state.Studies examining human post-mortem brain tissue found an increased number of microglia within AD patients with APOE ε4 5,6 . Minett et al. 7 found that increased microglia levels were negatively associated with AD pathology in non-demented individuals while the opposite was observed in demented individuals. Furthermore, APOE ε4 was associated with increased microglial activation and worse tau pathology and clinical outcomes 7 . In addition, peripheral low-grade inflammation was associated with risk of AD in APOE ε4, but not ε2 or ε3 carriers 8 . These studies suggest the APOE ε4 allele may lead to AD pathology through an altered inflammatory state. However, the precise role of APOE ε4 in modulating the relationship between microglia and inflammatory cytokines with the development of AD pathologies in the human brain is largely unknown.www.nature.com/scientificreports www.nature.com/scientificreports/ displayed a greater effect on dementia in APOE ε4 positive participants (OR = 12.188, p = 0.038) than in APOE ε4 negative participants (OR = 2.542, p = 0.001).Sensitivity analyses. In order to control for possible conf...

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