Rare APOE genetic variants reduce Alzheimer’s risk

Last Updated on June 28, 2022 by Joseph Gut – thasso

13 June 2022 – Sometimes, patients genetics can be bewildering and/or unjust. Common belief with patients and the general public would be that genetic variants would be responsible for causing all kinds of adverse drug reactions (ADR’s) and be at the base of of the susceptibility for the development of very many diseases, including cancer.

And then, you come across a study like the following which indicates that rare APOE genetic variants reduce the risk of patients for the development of Alzheimer’s disease by more than 60%. Two rare mutations in the APOE gene, namely APOE ε4 (R251G) and APOE ε3 (V236E), dramatically reduce the risk of developing Alzheimer’s disease (AD), results of a large genetic association study show.

APOE ε4 (R251G) is a newly identified, risk-modifying variant in APOE’s lipid binding region that is inherited with APOE ε4 and reduces the risk of AD by more than 60%. Evvectively, the APOE ε4 is the strongest genetic risk factor for late-onset AD, and identifying genetic variants counterbalancing its associated risk may shed new light on its role in driving AD. The findings in the present study may hopefully lead to the development of new drugs mimicking the effect of these genetic variants on APOE to reduce the impact of APOE ε4 on AD pathology..

The other variant, APOE ε3 (V236E), is co-inherited with APOE ε3 and reduces the risk of AD by more than 50%. It was previously shown to be associated with decreased AD in smaller cohorts, but now more robustly confirmed  in a much larger population.

Both R251G and V236E are missense variants that change a single amino acid in the APOE protein sequence. They are exceedingly rare; the estimated population frequency is less than 0.1%. To identify these rare protective variants, the researchers mined genetic data from multiple studies involving 544’384 individuals, including 67’896 people with AD, 28’484 proxy AD case persons (individuals with a first-degree relative with AD), and 340’306 healthy control persons.

The two variants were associated with a more than twofold reduction in AD risk, with an odds ratio of 0.44 for R251G and 0.37 for V236E. In addition, among V236E carriers, there was a 10.5-year delay in the age of AD onset compared with noncarriers; among R251G carriers, there was a trend toward a 6-year delay.  With both variants, the cumulative incidence of AD grew more slowly with age.

The researchers note that the location of these protective variants, i.e., near the carboxyl-terminal portion of APOE, adds support to studies suggesting that the C-terminal domain plays an important role in AD pathogenesis.

Interestingly, the APOE ε3 (V236E) and APOE ε4 (R251G)  genetic variants seem not to be the only variants protective against Alzheimer’s disease in that in earlier reports, similar findings were attributed to APP A673T, an allelic variant of the amyloid precursor protein (APP) gene.

See here a sequence on similar APOE gene effects in connection to ancestry; more than flabbergasting findings: