Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager‐horticulturalists with a high parasite burden

Trumble, Benjamin C.; Stieglitz, Jonathan; Blackwell, Aaron D.; Allayee, Hooman; Beheim, Bret; Finch, Caleb E.; Gurven, Michael; Kaplan, Hillard

doi:10.1096/fj.201601084r

Cited by 83 publications

(74 citation statements)

References 60 publications

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“…Although APOE4 mice are more vulnerable to AD-like pathology and exhibit generally poorer metabolic and inflammatory profiles than APOE3 mice, our observations suggest that female APOE4 mice can exhibit lesser perturbation to an environmental stressor and a corresponding resistance to further increases in pathology. This paradox of a relatively benign gene-environment interaction with APOE4 is consistent with recent observations in the foragerhorticulturist Tsimane population, in which APOE4 carriers showed maintained or improved cognition relative to APOE4 noncarriers challenged with high parasite and pathogen burden (70). Because sex impacts the effects of APOE as well as responses to metabolic and inflammatory stressors, it is likely that sex significantly impacts numerous interactions among AD risk factors.…”

Section: Discussionsupporting

confidence: 88%

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

Christensen

Pike

2018

FASEB j.

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Development of Alzheimer's disease (AD) is regulated by interactive effects of genetic and environmental risk factors. The most significant genetic risk factor for AD is the ε4 allele of apolipoprotein E (APOE4), which has been shown to exert greater AD risk in women. An important modifiable AD risk factor is obesity and its associated metabolic dysfunctions. Whether APOE genotype might interact with obesity in females to regulate AD pathogenesis is unclear. To investigate this issue, we studied the effects of Western diet (WD) on female EFAD mice, a transgenic mouse model of AD that includes human APOE alleles ε3 (E3FAD) and ε4 (E4FAD). EFAD mice were fed either control (10% fat, 7% sugar) or WD (45% fat, 17% sugar), and both metabolic and neuropathologic outcomes were determined. Although E4FAD mice generally exhibited poorer metabolic status at baseline, E3FAD mice showed greater diet‐induced metabolic impairments. Similarly, E4FAD mice exhibited higher levels of AD‐related pathology overall, but only E3FAD showed significant increases on select measures of β‐amyloid pathology after exposure to WD. These data demonstrate a gene–environment interaction between APOE and obesogenic diets in females. Understanding how AD‐promoting effects of obesity are modulated by genetic factors will foster the identification of at‐risk populations and development of preventive interventions.—Christensen, A., Pike, C. J. APOE genotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice. FASEB J. 33, 4054–4066 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 88%

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

Christensen

Pike

2018

FASEB j.

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“…We speculate that the environment today has changed in such a way that has made this allele more deleterious recently. For example, it has been proposed that the evolution of this allele has been influenced by changes in physical activity [60] and parasite burden [61]. Considering 42 traits that have been investigated by GWAS, we found a number of cases in which the mean polygenic score changes with age.…”

Section: Discussionmentioning

confidence: 91%

Identifying genetic variants that affect viability in large cohorts

Mostafavi

Berisa

Przeworski

et al. 2016

Preprint

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A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we find only a few common variants with large effects on age--specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence one of 42 traits, we detect a number of strong signals. In participants of the UK Biobank study of British ancestry, we find that variants that delay puberty timing are enriched in longer--lived parents (~6×10 '( for fathers and ~2×10 '* for mothers), consistent with epidemiological studies. Similarly, in mothers, variants associated with later age at first birth are associated with a longer lifespan (~1×10 '* ). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease, body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non--British ancestry. Moreover, we see marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of coronary artery disease and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical datasets can be used to learn about selection effects in contemporary humans.

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“…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].…”

Section: Discussionmentioning

confidence: 99%

“…Three studies reported improved performance in spatial tasks in 4 carriers [102,119,120]. A large British study (3/4 = 542, 4/4 = 43) showed faster reaction times in association with the 4 allele [121].…”

Section: Mental Performance In Young Apolipoprotein 4 Carriers (Table 8)mentioning

confidence: 99%

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

Smith

Ashford

Perfetti³

2019

JAD

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Inheritance of a single copy of the apolipoprotein E (APOE) 4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to 3 allele homozygosity. There is a decreased risk associated with the APOE 2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous 4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on 4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the 4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral 4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing 3 allele, at the expense of decreased fitness in old age, which is substantially improved by the 3 allele. However, possession of the 4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion. conceptualization of AD pathology dates from 1968 when Blessed et al. showed in elderly individuals that the NFTs correlated with the severity of the dementia, though the neuritic plaques, which contain cerebral amyloid-␤ (A␤), did not [2]. A major advance in understanding AD pathology was the demonstration that AD pathology predominantly affects the posterior-temporal, inferior parietal, posterior cingulate, and medial temporal region [3], with a characteristic pattern of progression beginning in the entorhinal cortex involving neurofibrillary (NF)

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Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager‐horticulturalists with a high parasite burden

Cited by 83 publications

References 60 publications

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

Identifying genetic variants that affect viability in large cohorts

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

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