Evolution of genetic variations that protect against Alzheimer's and cardiovascular diseases

In the October issue of The American Journal of Human Genetics, researchers present evidence that human evolution has led to a decrease in the prevalence of certain genetic variations that are associated with an increased risk for Alzheimer's disease and cardiovascular disease. All human populations studied to date show variation at the APOE locus, which encodes apolipoprotein E. The three common variants of APOE, e2, e3, and e 4, differ in their associated risk with both cardiovascular and Alzheimer's disease. Individuals possessing an e4 allele have an increased risk of both diseases, while e2 is protective.

In this work by Fullerton et al., the authors discovered considerable differences in the population-specific distribution of APOE variation. Careful analysis of these population differences allowed them to trace the history of APOE variation. It appears that the high-risk e4 is the ancestral variant, but that the e3 variant has risen in frequency in the last 200,000 years. The authors hypothesize that this change in APOE variation may have resulted from an advantageous mutation that is present in the e3, and the related e2, variants of APOE. Since Alzheimer's and cardiovascular diseases generally afflict individuals who have passed reproductive age, these diseases probably do not play a role in the selection against the high risk e4 APOE variant. However, the normal function of APOE affects several important processes in the body, including lipid absorption, immunity, and nerve growth. Perhaps a detrimental effect on one of these functions has led to selection at the APOE locus, which may have inadvertently led to the spread of the allele that is protective for Alzheimer's and cardiovascular diseases.

For the full text of this article entitled "Apolipoprotein E variation at the sequence haplotype level: Implications for the origin and maintenance of a major human polymorphism" by Fullerton et al., please see the electronic edition of the October issue of The American Journal of Human Genetics at www.ajhg.org.

For further information, contact the corresponding author: Stephanie Fullerton, Institute of Molecular Evolutionary Genetics, Dept. of Biology and Dept. of Anthropology, Pennsylvania State University. Phone: 814-865-2715. Fax: 814-865-9131. Email: smf15@psu.edu.

Contributed by: Kate Beauregard, The American Journal of Human Genetics. Phone: 404-712-9985. Email: kbeaure@emory.edu.