Effect of APOE ε4 allele on survival and fertility in an adverse environment.
The apolipoprotein-ε4 allele (APOE-ε4) is strongly associated with detrimental outcomes in affluent populations including atherosclerotic disease, Alzheimer's disease, and reduced lifespan. Despite these detrimental outcomes, population frequencies of APOE-ε4 are high. We hypothesize that the high frequency of APOE-ε4 was maintained because of beneficial effects during evolution when infectious pathogens were more prevalent and a major cause of mortality. We examined a rural Ghanaian population with a high pathogen exposure for selective advantages of APOE-ε4, to survival and or fertility. METHODS AND FINDINGS: This rural Ghanaian population (n = 4311) has high levels of mortality from widespread infectious diseases which are the main cause of death. We examined whether APOE-ε4 was associated with survival (total follow-up time was 30,262 years) and fertility after stratifying by exposure to high or low pathogen levels. Households drawing water from open wells and rivers were classified as exposed to high pathogen levels while low pathogen exposure was classified as those drawing water from borehole wells. We found a non-significant, but positive survival benefit, i.e. the hazard ratio per APOE-ε4 allele was 0.80 (95% confidence interval: 0.69 to 1.05), adjusted for sex, tribe, and socioeconomic status. Among women aged 40 years and older (n = 842), APOE-ε4 was not associated with the lifetime number of children. However, APOE-ε4 was associated with higher fertility in women exposed to high pathogen levels. Compared with women not carrying an APOE-ε4 allele, those carrying one APOE-ε4 allele had on average one more child and those carrying two APOE-ε4 alleles had 3.5 more children (p = 0.018). CONCLUSIONS: Contrary to affluent modern-day populations, APOE-ε4 did not carry a survival disadvantage in this rural Ghanaian population. Moreover, APOE-ε4 promotes fertility in highly infectious environments. Our findings suggest that APOE-ε4 may be considered as evolutionarily adaptive. Its adverse associations in affluent modern populations with later onset diseases of aging further characterize APOE-ε4 as an example of antagonistic pleiotropy.
Department of Psychiatry, VU University Medical Center/GGZinGeest, Amsterdam, the Netherlands. EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, the Netherlands. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. Leyden Academy on Vitality and Ageing, Leiden, the Netherlands. University of Melbourne, Melbourne Academic Center of Health, Melbourne, Australia. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands. Department of Clinical Laboratory Sciences, School of Medicine and Health Sciences, University for Development Studies, Tamale, Ghana. Davis School of Gerontology and Dornsife College, Dept Biological Sciences, University of Southern California, Los Angeles, United States of America. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. Leyden Academy on Vitality and Ageing, Leiden, the Netherlands. Department of Public Health, and Center for Healthy Ageing, University of Copenhagen, Copenhagen, Denmark.
