Alzheimer’s disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors. The apolipoprotein E (APOE) allele e4 imparts a dramatic increase in the risk of developing Alzheimer’s disease, but the exact mechanism of this relationship is unknown. The e4 allele is associated with increased Ab plaques, neurofibrillary tangles, and a heightened inflammation state, all pathological hallmarks of Alzheimer’s disease. To test the hypothesis that microglia and related cytokines were differentially associated with Alzheimer’s disease pathology based on the presence of e4, we compared individuals with and without the APOE e4 allele within a community based aging cohort (n = 186). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology as measured by AT8 immunostaining (B = 0.459, p = 0.028) in e4 positive participants but not in e4 negative participants. Analysis of cytokines implicated in AD, i.e. IL-10, IL-13, IL-4, IL-1a, revealed a significant negative association with AT8 in e4 negative participants. The association of the anti-inflammatory cytokines IL-10, IL-13, and IL-4 on tau pathology appeared to be mediated by ApoE protein levels, suggesting that these cytokines and the ApoE protein may interact to prevent increased tau pathology within e4 negative individuals. The pro-inflammatory cytokine, IL-1, was negatively associated with AT8 (B = -0.241, p = 0.009) independent of Ab1-42 in e4 negative participants but not in e4 positive participants, suggesting a potential novel protective association. Overall, in e4 negative participants, elevated levels of IL-10, IL-13, IL-4, IL-1a are associated with less tau pathology. These associations are largely absent in the presence of e4 where tau pathology is significantly associated with microglial cell density. Taken together, these results suggest that APOE e4 mediates an altered inflammatory response and increased tau pathology independent of Ab pathology. / 2019-07-03T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/30748 |
| Date | 03 July 2018 |
| Creators | Friedberg, Jacob Sands |
| Contributors | Levy, Simon, Stein, Thor |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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