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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Evidence suggests that low carbohydrate (<130 g/day of carbohydrate) (LCD) and very low carbohydrate, ketogenic diets (typically <50 g/day of carbohydrate) (VLCKD) can be effective tools for managing diabetes given their beneficial effects on weight loss and glycemic control. VLCKD also result in favorable lipid profile changes. However, these beneficial effects can be limited by poor dietary adherence. Cultural, religious, and economic barriers pose unique challenges to achieving nutritional compliance with LCD and VLCKD. We review the various methods for assessing adherence in clinical studies and obstacles posed, as well as potential solutions to these challenges.

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