Effect of APOE ε4 allele on survival and fertility in an adverse environment

Abstract

BackgroundThe 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 findingsThis 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).ConclusionsContrary 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.

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

“…The weight-of-the-evidence presented in Tables 1-8 supports the hypothesis that the possession of the 4 allele in youth may have a positive differential impact on fitness during different life stages [145]. Young subjects having at least one copy of the 4 allele reportedly possess a number of advantages that might facilitate survival in harsh environments including the following among others: more rapid improvement in VO 2max following exercise [51]; increased fertility at high pathogen burdens [52,53]; more rapid infant development [105]; prophylaxis against cognitive deficits associated with severe diarrhea [122][123][124]; resistance to certain infections, e.g., hepatitis [76] and malaria [83]; faster reaction times [121]; better spatial memory [111,102,119,120]; and slight superiority in direct or indirect measures of IQ [135,134,126,141]. Some of these advantages appear to come at the expense of differences in neural processing that might place higher metabolic demands per unit time on the brains of young 4 carriers [143,111,96].…”

“…A limited number of studies have examined potential associations between APOE 4 carrier status and fertility. In 2017, van Exel et al [52] studied 100 women with a history of at least two firsttrimester recurrent miscarriages in Tabriz, Iran, and 100 healthy women with at least two successful pregnancies and no miscarriages. This study incorporated 31 4 carriers and showed that APOE 4 was associated with higher fertility in women exposed to high pathogen levels.…”

Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework

“…APOE-e4 is also associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden 181 , thus conferring an advantage in a specific environment. This and other results led to the hypothesis that the high frequency of APOE-e4 was maintained since it confers protection in environments where infectious diseases are a relevant cause of mortality 182 . APOE gene also influences fertility and APOE-e4 positive women had have significantly higher levels of mean luteal progesterone, suggesting increased fertility, that can contribute to explain the conservation among different populations of this "deleterious" allele 183 .…”

Characterizing the human APOE epsilon 4 knock-in transgene in female and male rats with multimodal magnetic resonance imaging

“…The frequency of Ɛ4 allele is highest in non-industrialized populations in equatorial and tropical areas [94]. In rural Ghana and Ecuador, Ɛ4 carriers show a significant gene effect for increased fertility and survival of offspring in the face of a high infectious load [95,96]. It is hypothesized that the Ɛ4 isoform provides high levels of cholesterol precursor to ovaries for progesterone and estrogen synthesis for enhanced reproductive fertility [97].…”