The few people who carry two copies of the ApoE2 allele are blessed with remarkable protection against Alzheimer’s disease, according to a study published February 3 in Nature Communications. While the E2 allele has long been known to hedge AD risk, the new study used data from more than 5,000 neuropathologically confirmed AD cases and controls to make the most informed assessment of the allele’s protective capacity yet.
The study garnered data from the Alzheimer’s Disease Genetics Consortium’s 4,018 neuropathologically confirmed AD dementia cases and 989 cognitively normal controls, and calculated risk comparisons between all possible genotypes. E2 homozygotes faced a third of the AD risk that E2/E3 heterozygotes did, and 87 percent lower risk than people with the most common genotype, E3/E3. Compared with the E4 homozygotes—those at highest risk for the disease—E2 homozygotes had 99.6 percent lower odds. Findings from a larger cohort of more than 24,000 clinical AD cases and controls, though without neuropathological confirmation, fell along the same lines but underestimated ApoE2’s protective prowess.
Among ApoE2 carriers who did develop AD, the allele associated with an older age at onset, and a lower tau tangle burden, even after controlling for neuritic Aβ plaques.
“We think [our study] will remind stakeholders, including drug developers, that APOE and its variants may have a greater impact on the differential risk of AD and ensuing dementia than previously appreciated, and that it will underscore the opportunity to develop APOE-modifying drugs to treat and prevent AD,” wrote Reiman.—Jessica Shugart
- Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, Chen Y, Su Y, Myers AJ, Hardy J, Paul Vonsattel J, Younkin SG, Bennett DA, De Jager PL, Larson EB, Crane PK, Keene CD, Kamboh MI, Kofler JK, Duque L, Gilbert JR, Gwirtsman HE, Buxbaum JD, Dickson DW, Frosch MP, Ghetti BF, Lunetta KL, Wang LS, Hyman BT, Kukull WA, Foroud T, Haines JL, Mayeux RP, Pericak-Vance MA, Schneider JA, Trojanowski JQ, Farrer LA, Schellenberg GD, Beecham GW, Montine TJ, Jun GR, Alzheimer’s Disease Genetics Consortium. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020 Feb 3;11(1):667. PubMed.