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The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-\u03b54 significantly increases AD risk, APOE-\u03b53 is the most common gene variant, and APOE-\u03b52 protects against AD. However, the underlying mechanisms of APOE-\u03b54 on AD risk remains unclear, with APOE-\u03b54 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-\u03b53\/3 (n\u2009=\u20099) or APOE-\u03b54\/4 (n\u2009=\u200910) participants with AD pathology and APOE-\u03b53\/3 (n\u2009=\u20099) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-\u03b54\/4-AD individuals compared to APOE-\u03b53\/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-\u03b53 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-\u03b54 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.<\/jats:p>","DOI":"10.1093\/jnen\/nlab085","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T21:43:56Z","timestamp":1630964636000},"page":"922-932","source":"Crossref","is-referenced-by-count":29,"title":["Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status"],"prefix":"10.1093","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1208-8607","authenticated-orcid":false,"given":"Courtney M","family":"Kloske","sequence":"first","affiliation":[{"name":"From the Department of Physiology, Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5783-3781","authenticated-orcid":false,"given":"Adam J","family":"Dugan","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1252-6547","authenticated-orcid":false,"given":"Erica M","family":"Weekman","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9412-9697","authenticated-orcid":false,"given":"Zachary","family":"Winder","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ela","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter T","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7207-4696","authenticated-orcid":false,"given":"David W","family":"Fardo","sequence":"additional","affiliation":[{"name":"Department of Biostatics, Sanders-Brown Center on Aging, College of Public Health, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3388-1564","authenticated-orcid":false,"given":"Donna M","family":"Wilcock","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"2024032523420296400_nlab085-B1"},{"key":"2024032523420296400_nlab085-B2","volume-title":"2021 Alzheimer\u2019s Disease Facts and Figures"},{"key":"2024032523420296400_nlab085-B3","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/S0140-6736(96)10203-8","article-title":"Alzheimer\u2019s 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