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Possession of the ε4 allele of apolipoprotein E ( APOE ) is the primary genetic risk factor for the sporadic form of Alzheimer’s disease (AD). While researchers have extensively characterized the impact that  APOE  ε4 ( APOE4 ) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are  APOE4  carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between  APOE4 -positive ( APOE4 +) vs.  APOE4 -negative ( APOE4 −) AD patients. The studies performed on this topic to date suggest that  APOE4  is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically,  APOE4 + AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to  APOE4 − AD patients. On the other hand,  APOE4 − AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to  APOE4 + AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between  APOE4 + vs.  APOE4 − AD patients suggest that there is a fundamental divergence in AD manifestation related to  APOE  genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.

APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review