Notable: Alzheimer’s risk and genetic background of ApoE

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Notable paper: Rajabli F, Feliciano BE, Celis K, Hamilton-Nelson KL, Whitehead PL, Adams LD, et al. (2018) Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet 14(12): e1007791. doi:10.1371/journal.pgen.1007791

Synopsis: Rajabli and coworkers examined late-onset Alzheimer’s disease risk in a large sample (~5500) African-American cases and controls, and a smaller number (~400) Puerto Ricans. Their goal was to understand how the APOE ε4 allele contributes to disease risk in these samples. They found that the effect of the ε4 allele in individuals with a specifically African genetic background for that allele is reduced compared to other genetic backgrounds. The genome-wide proportion of African ancestry did not correlate with this effect. They infer that there are likely one or more protective mutations linked to the ε4 allele in Africans.

Interesting because: The APOE gene is the most well-known (and largest) risk locus for Alzheimer’s disease. The ε4 allele carries the risk, while alternative alleles are protective. The polymorphism among these alleles is quite ancient in humans; these different variants of APOE have been around for a long time. This raises the question of how this polymorphism has persisted, if one of the alleles has a strong disease risk. It has long been known that the disease risk of ε4 is lower in people of African descent, but exactly why the allele should have less of an effect in that group has not been clear. Some geneticists argued for a genetic background interaction, where one or more modifier genes might increase risk in non-African genetic backgrounds, or decrease risk in African genetic backgrounds. This new study shows it is not the overall genome that matters; it is specifically the haplotype of ε4. It remains to find the mutations on African ε4 haplotypes that modify disease risk.

Evolutionary connections: If I remember correctly, the ε4 allele is more like the ancestral condition for humans, but it does not characterize other great apes. That is, at some point in our evolutionary history, the ε4 allele arose. Today it carries an Alzheimer’s risk, but this may have been near insignificant in ancestral hominins with much shorter average lifespans. Some have speculated that APOE was under selection when hominins first became meat eaters. Exactly what is going on in this system is not obvious to me, but it is an interesting mystery.