Imagine if understanding the protective effects of Apolipoprotein E (APOE) genotype e2 was like uncovering the hidden gems in a treasure chest. In this comprehensive review, we delve into the associations between APOE-e2 and longevity, cognition, neuroimaging, and neuropathology in humans. By unraveling the limits of e2’s shielding powers, we may unlock potential therapeutic avenues for preventing or alleviating Alzheimer’s disease (AD). Analyzing studies from 1994 to 2021, we selectively review research on human subjects and focus on e2 observations. Interestingly, while e2 appears to offer robust protection against AD neuropathologies and influences longevity, its impact on cognition and other AD imaging markers remains inconclusive due to inconsistent findings. However, it’s worth noting that e2 is linked to an increased risk of non-AD proteinopathies and a less favorable cerebrovascular profile. Additionally, we discovered several methodological weaknesses in brain function and cognition studies that may have contributed to these conflicting and potentially misleading results. Considering these factors, we provide careful interpretations of existing findings and propose research strategies to effectively explore the independent and unbiased effect of e2 on AD risk.

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’s protective effects—and their limits—could be elucidated, it could offer therapeutic windows for Alzheimer’s disease (AD) prevention or amelioration. Literature examining e2 within the years 1994–2021 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’s 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.

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