Humanin P3S, haplogroup N1b and the risk of Alzheimer's disease

A commentary of the paper ‘Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology’ that appeared recently in Aging Cell. The possible association of a mitochondrial haplogroup with a disease is frequently discussed. The Humanin peptide encoded by the mtDNA has been shown to play an important regulatory role in cell metabolism. There are variants of Humanin caused by different mutations and it is known that the potent form of Humanin, termed S14G, is found naturally in the people of haplogroup U6a7a1a because they have the mutation m.A2672G; however it has not been shown that having this mutation is indeed beneficial. In their paper, the authors suggest that the mitochondrial DNA mutation, m.C2639T, may be beneficial in people who are in haplogroup N1b and also carry APOE4. The mutation changes the common form of Humanin to Humanin P3S. In the study, the researchers looked at a group of Ashkenazi women who were over the age of 95, and found that a higher proportion of them carried APOE4, suggesting that Humanin P3S protected them against the adverse effects of APOE4. A study in a mouse model supported this finding by showing treatment with Humanin P3S reduced APOE4-induced brain pathology. In the world population, there are about 500,000 Ashkenazi in haplogroup N1b, predominantly in the subgroup N1b1b1; and there are about 9.5 million non-Ashkenazi people with the mutation m.C2639T and are therefore also in haplogroup N1b and have Humanin P3S. However, the researchers have yet to show Humanin P3S is of benefit in non-Ashkenazi people. This paper raises the possibility of a therapeutic use of Humanin P3S in the treatment of Alzheimer's disease.