Apolipoprotein E Genotype e2: Neuroprotection and Its Limits

Abstract

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.

Keywords: APOE e2; Alzheimer’s disease; biomarkers; cognition; neuropathology; neuroprotection.

FIGURE 1

Mechanisms. This figure is a speculative but neurobiologically plausible mechanistic model of how two established molecular properties of the e2 isoform, namely its protein abundance and its low affinity for the LDLR receptor, might provide initial stages of neuroprotection. While mRNA levels of the isoforms appear to be equivalent (Conejero-Goldberg et al., 2014), post translational differences due to isoform related susceptibility to cleavage or other degradation related processes result in full-length protein level differences (Riddell et al., 2008; Mahley, 2016). The mechanistic interpretation of such differences in brain are not established: Speculatively, protein abundance may have advantageous effects in and of itself by way of clearance of Ab, including via the BBB, or delivery of cholesterol to neurons for synaptic maintenance. As a caveat to this, the e4 isoform may be “toxic,” so simply increasing abundance might not be advantageous. Second, neuroprotective effects may be associated with reduced binding at a primary cellular ApoE receptor, LDLR, with the corollary that more ApoE e2 is more available at other receptors, such as LRP1 or ApoER2 and in parallel, allow other ligands to stimulate the LDLR receptor. These and other upstream (e.g., promoter variants) and downstream factors (e.g., isoform specific differences in lipidation, microglial activation, LTP reduction, etc.) are discussed elsewhere.

FIGURE 2

APOE genotype and neuropathology. (A) Association of APOE genotype and diffuse amyloid plaque extent (Thal phase). Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. There are increasing proportions of the most severe pathology (plaque stage 5) from the e2 to e4/e4 genotype groups in stepwise fashion. Stage 1 includes one or more neocortical regions with Ab immunopositivity, stage 2 includes hippocampal positivity, and stages 3–5 include other limbic and subcortical structures. Amyloid stage 0 = no pathology; stage 5 = widespread cortical, limbic, and subcortical pathology. Stages 1 and above are consistent with AD. The total N = 1,557. Reproduced with permission Goldberg et al. (2020a). (B) Association of APOE genotype and Braak stage. Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. There are increasing proportions of the most severe pathology (Braak stages 5 and 6 from the e2 to e4/e4 genotype groups in stepwise fashion. Braak stage characterizes the spread of neurofibrillary tangle pathology from entorhinal cortex (stages 1 and 2), to increasing involvement of the hippocampus (stages 3 and 4), to neocortical involvement (stages 5 and 6) (Braak stage 0 = no pathology; stage 6 = severe neocortical pathology. Stages 3 and above are consistent with AD. The total N = 1,557. Reproduced with permission Goldberg et al. (2020a).