Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E \u03b54 genotype

Jacob S Friedberg,Rhoda Au,Rhoda Au,Gyungah Jun,Victor E Alvarez,Victor E Alvarez,Nurgul Aytan,Oliver J Standring,Oliver J Standring,Jonathan D Cherry,Jonathan D Cherry,Hoon Ryu,Hoon Ryu,Sarah Svirsky,Sarah Svirsky,Gaoyuan Meng,Thor D Stein,Thor D Stein,Thor D Stein,Weiming Xia,Raymond Nicks

doi:10.1038/s41598-020-59869-5

Jacob S Friedberg, Rhoda Au + Show 19 more

Open Access

https://doi.org/10.1038/s41598-020-59869-5

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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 Aβ1–42 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 Aβ1–42 pathology.

Highlights

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation
To test whether there was an effect of an interaction between apolipoprotein E (APOE) ε4 genotype and sex on tau pathology, a two-step linear regression adjusting for sex, APOE ε4, and sex-APOE ε4 interaction term was performed
This suggests that the effect of APOE ε4 on tau pathology is independent of sex

Summary

Introduction

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. 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. 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. The role of microglia in attenuating or facilitating the development of AD pathologies may be mediated by the specific factors they release and the balance between pro-inflammatory and anti-inflammatory cytokines. We sought to test the hypothesis that the presence of the APOE ε4 allele alters the interaction between microglia and associated cytokines with AD pathology

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