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Aging Neurosci."],"abstract":"<jats:p>In this review, we comprehensively, qualitatively, and critically synthesized several features of APOE-e2, a known APOE protective variant, including its associations with longevity, cognition, and neuroimaging, and neuropathology, all in humans. If e2\u2019s protective effects\u2014and their limits\u2014could be elucidated, it could offer therapeutic windows for Alzheimer\u2019s disease (AD) prevention or amelioration. Literature examining e2 within the years 1994\u20132021 were considered for this review. Studies on human subjects were selectively reviewed and were excluded if observation of e2 was not specified. Effects of e2 were compared with e3 and e4, separately and as a combined non-e2 group. Our examination of existing literature indicated that the most robust protective role of e2 is in longevity and AD neuropathologies, but e2\u2019s effect on cognition and other AD imaging markers (brain structure, function, and metabolism) were inconsistent, thus inconclusive. Notably, e2 was associated with greater risk of non-AD proteinopathies and a disadvantageous cerebrovascular profile. We identified multiple methodological shortcomings of the literature on brain function and cognition that could have contributed to inconsistent and potentially misleading findings. We make careful interpretations of existing findings and provide directions for research strategies that could effectively examine the independent and unbiased effect of e2 on AD risk.<\/jats:p>","DOI":"10.3389\/fnagi.2022.919712","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T01:07:25Z","timestamp":1657760845000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":40,"title":["Apolipoprotein E Genotype e2: Neuroprotection and Its Limits"],"prefix":"10.3389","volume":"14","author":[{"given":"Hyun","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davangere P.","family":"Devanand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Carlson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry E.","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1093\/aje\/kws004","article-title":"20\/20\u2013Alcohol and age-related macular degeneration: the Melbourne Collaborative Cohort Study.","volume":"176","author":"Adams","year":"2012","journal-title":"Am. 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