Association of Rare APOE Missense Variants R189C and W276C With Risk of Alzheimer Disease
Le Guen, Y.; Reil, D.; Jackson, R. J.; Pena-Tauber, A.; Khosla, C.; Greicius, M. D.
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Rare APOE missense variants in admixed populations can clarify mechanisms of Alzheimer disease (AD) risk beyond {varepsilon}2 and {varepsilon}4. We analyzed APOE coding variation in the Alzheimer disease Sequencing Project and AllofUs and meta-analyzed ancestry-adjusted case-control associations. Two {varepsilon}3-linked variants enriched in Native American ancestry among Admixed American individuals were associated with AD: R189C increased risk (odds ratio (OR), 3.35; 95% confidence interval (CI), 1.25-9.00; P = 0.016), whereas W276C was protective (OR, 0.28; 95% CI, 0.10-0.82; P = 0.020). In a nascent ApoE secretion assay that resolves high molecular weight lipid-bound species from lipid-poor species, R189C showed an APOE-{varepsilon}4-like shift toward the lipid-bound fraction. In an orthogonal self-association assay, W276C reduced ApoE self-association to the protective APOE-Jacksonville variant level. These findings expand the spectrum of APOE missense variants that are associated with AD and implicate C-terminal ApoE conformation and lipidation states as tractable mechanisms for pathogenesis and therapeutic targeting.
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