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APOE ε2 gene variant packs protective punch against Alzheimer’s disease

When it comes to the APOE gene and Alzheimer’s disease, the risk-increasing APOE ε4 variant often takes center stage, but there’s much more to the APOE genetic risk story. The APOE ε2 variant appears to lower risk, and having two copies of this variant may lower risk even more than previously thought, according to a study supported in part by NIA and published in Nature Communications.

DNA moleculeAPOE is a gene involved in making apolipoprotein E, a protein that helps carry cholesterol and other fats in the bloodstream. It comes in three forms, or alleles: APOE ε4 increases Alzheimer’s risk, APOE ε3 is believed to play a neutral role, and the relatively rare APOE ε2 has been associated with lower risk. Each person inherits two APOE alleles, one from each biological parent.

A team of researchers wanted to better understand the role of APOE ε2 in Alzheimer’s disease risk. They calculated risk estimates based on data from 4,018 autopsy-confirmed Alzheimer’s dementia cases and 989 controls obtained through the NIA-funded Alzheimer’s Disease Genetics Consortium (ADGC). As expected, only a small number of the cases, 24, had two copies of APOE ε2, but, compared with other genotypes, those with two copies were much less likely to have Alzheimer’s disease. Among the autopsy-confirmed cases, individuals with two copies of ε2 had a 66% risk reduction compared with people with one copy of ε2 and one copy of ε3, an 87% risk reduction compared to people with two copies of ε3, and a 99.6% risk reduction compared to people who had two copies of ε4.

The researchers also calculated risk estimates in an ADGC cohort of 23,857 participants (10,430 probable Alzheimer’s dementia cases and 13,426 controls). Two copies of APOE ε2 were still associated with a lower risk in this group, but the risk was not as low as in the autopsy-confirmed cases. The researchers attribute this to the fact that the autopsy-confirmed cases didn’t include any instances of misdiagnoses and suggest that the lower risk estimates seen in the neuropathologically confirmed sample may mean an even stronger protective effect from two copies of APOE ε2 than previously found.

In addition, those with two copies of APOE ε2 or one copy of APOE ε2 and one copy of APOE ε3 who did develop Alzheimer’s disease had a later age of onset and lower levels of amyloid-beta plaques and tau tangles, supporting previously known effects of APOE genotypes on these hallmarks of Alzheimer’s disease.

Findings point to the importance of clarifying the effect of APOE genotypes on Alzheimer’s pathology and exploring this avenue for potential treatments and preventions. For example, future research might investigate how to replicate the protective effects through gene editing or protein modification.

Although this study was conducted using a relatively large sample, few cases of two copies of APOE ε2 were identified (110 across both the autopsy-confirmed cases and clinical cohort), resulting in low statistical power, and participants were mainly white, so results aren’t generalizable to other groups. Additionally, to clarify the absolute lifetime risk of Alzheimer’s disease for each APOE genotype, cohort studies that include people with and without cognitive impairment and a neuropathological diagnosis are needed, the researchers note.

This study underscores the need to better understand the molecular mechanisms by which APOE ε2 lowers the risk of disease and/or delays its onset so they can be harnessed to develop better strategies for treatment and prevention. NIA has identified this as a research area of strategic importance and since 2017 has invested in projects aimed at understanding the role of APOE ε2 in aging and Alzheimer’s disease. These projects have been solicited through a series of targeted funding initiatives (PAR-16-370/PAR-16-371, RFA-AG-17-056/RFA-AG-18-022).

This research was funded in part by NIA grants RF1AG057519, R01AG15819, R01AG17917, R01AG031581, RC2AG036528, R01AG048927, R01AG032990, RF1AG051504, U01AG046139, R01AG030653, R01AG041718 and U01AG006781; P30AG19610 for the Arizona Alzheimer’s Disease Core Center; P30AG10161 for the Rush Alzheimer’s Disease Center; U01AG032984 for the Alzheimer’s Disease Genetics Consortium; U24AG041689 for the NIA Genetics of Alzheimer’s Disease Data Storage Site; P50AG005133 to the University of Pittsburgh Alzheimer's Disease Research Center (ADRC); and P50AG005136 to the University of Washington ADRC.

These activities relate to NIA’s AD+ADRD Research Implementation Milestone 2.E, “Create cross-disciplinary research programs aimed at understanding the integrative physiology of APOE and its pharmacogenetic effects on various pharmacological and non-pharmacological interventions.”

Reference: Reiman et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nature Communications. 2020;11(1):667. doi: 10.1038/s41467-019-14279-8.