Is ApoE the piece to complete the puzzle of Alzheimer’s disease?

Apolipoprotein-E (ApoE), with three human isoforms designated APOE2, APOE3, and APOE4, is a multifunctional protein known to be involved in lipid transport. It has attracted much attention due to its association with late-onset Alzheimer’s disease (AD) (i.e., APOE4), atherosclerosis, and other inflammatory conditions. Though ApoE is capable of different activities depending on the local tissue milieu, its primary functional mechanism has remained enigmatic. In a recent Nature Medicine study (1), Yin et al. used multiple in vitro and in vivo approaches, including mouse models and human brain, choroid plexus (ChP), and carotid artery tissue analyses, to link ApoE to the classical complement cascade (CCC) through complex formation between ApoE and activated C1q. The authors found evidence of CCC activation in the ChP of ApoE-/- mice, and in vitro CCC inhibition in the presence of ApoE. Interestingly, C1q could be bound by all three ApoE isoforms. On examination of human AD brain tissue, there was a correlation between cognitive decline and ChP C1q-ApoE complexes as well as detection of the complexes in AD plaques. The researchers also presented data that a similar process may underlie atherosclerosis. Thus, the paper identifies a major function of ApoE as a checkpoint inhibitor of the CCC in the context of the C1q-ApoE complex, and offers novel perspective of the biology underlying AD, atherosclerosis, and potentially other inflammatory diseases.

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