Curious Dichotomies of Apolipoprotein E Function in Alzheimer’s Disease and Cancer—One Explanatory Mechanism of Inverse Disease Associations?

An apparent “inverse” relationship exists between two seemingly unconnected conditions, Alzheimer’s disease (AD) and cancer, despite sharing similar risk factors, like increased age and obesity. AD is associated with amyloid beta (Aβ) plaques and neurofibrillary tau tangles that cause neural degeneration; cancer, in contrast, is characterized by enhanced cell survival and proliferation. Apolipoprotein E (ApoE) is the main lipoprotein found in the central nervous system and via its high affinity with lipoprotein receptors plays a critical role in cholesterol transport and uptake. ApoE has 3 protein isoforms, ApoE E2, ApoE E3, and ApoE E4, respectively encoded for by 3 allelic variants of APOE (ε2, ε3, and ε4). This review examines the characteristics and function of ApoE described in both AD and cancer to assimilate evidence for its potential contribution to mechanisms that may underly the reported inverse association between the two conditions. Of the genetic risk factors relevant to most cases of AD, the most well-known with the strongest contribution to risk is APOE, specifically the ε4 variant, whereas for cancer risk, APOE has not featured as a significant genetic contributor to risk. However, at the protein level in both conditions, ApoE contributes to disease pathology via affecting lipid physiology and transport. In AD, Aβ-dependent and -independent interactions have been suggested, whereas in cancer, ApoE plays a role in immunoregulation. Understanding the mechanism of action of ApoE in these diametrically opposed diseases may enable differential targeting of therapeutics to provide a beneficial outcome for both.