APOE genotype, hippocampus, and cognitive markers of Alzheimer's disease in American Indians: Data from the Strong Heart Study

Abstract

Background:The apolipoprotein E (APOE) ε4 allele confers higher risk of neurodegeneration and Alzheimer's disease (AD), but differs by race/ethnicity. We examined this association in American Indians. Methods: The Strong Heart Study is a population-based cohort of American Indians who were 64 to 95 years of age in 2010 to 2013. APOE ε4 status, brain imaging, and neuropsychological testing was collected in N = 811 individuals. Summary statistics, graphics, and generalized linear regressions-adjusted for sociodemographics, clinical features, and intracranial volume with bootstrap variance estimator-compared APOE ε4 carriers with non-carriers.Results: APOE ε4 carriers comprised 22% of the population (0.7% homozygotes). Participants were mean 73 years, 67% female, and 54% had some college education. The majority were obese (>50%), hypertensive (>80%), and diabetic (>50%). Neither imaging findings nor multidomain cognitive testing showed any substantive differences between APOE ε4 carriers and non-carriers. Conclusion:We found no evidence of neurodegenerative risk from APOE ε4 in American Indians. Additional studies are needed to examine potential protective features.

Neuropathology-basedAPOEgenetic risk score better quantifies Alzheimer’s risk

“…Disparities in the APOE ε4 genetic effect on AD risk have been observed in other populations. Although studies of Chinese patients show that APOE ε4 increases risk for AD similar to NHW [52,53], a study of neuroimaging and cognitive testing from 811 American Indians in the Strong Heart Study found no evidence of increased risk from APOE ε4 [54].…”

“…study that provided OR used to derive the APOE-npscore consisted of NHW individuals [12] and the cohorts included in our analyses comprised >94% NHW participants. With reported disparities in biomarker outcomes and in APOE genetic risk, there is evidence our findings may not translate directly to other populations [43][44][45][46][47][48][49][50][51][52][53][54]. Self-identified non-Hispanic Black (NHB) individuals are at a greater risk of AD dementia than NHW; however, even though APOE ε4 is more common in African genetic ancestry (rs429358 MAF: 0.26 in AFR vs. 0.14 in EUR), studies suggest APOE ε4 has a weaker effect, or no effect, on AD dementia in NHB individuals [45][46][47][48][49].…”

Long Covid and Neurodegenerative Disease

“…But as worrisome as that might seem, AD appears to be less genetic and more epigenetic. The native American Indian population presents plenty of APOE4 but very little Alzheimer's disease 141 . The Paleolithic diet provides an excellent Ca:Mg balance.…”

Demand Coupling Drives Neurodegeneration: A Model of Age-Related Cognitive Decline and Dementia

“…Abundant evidence indicates that the late-onset form of AD results from a complex mix of gene–environment interactions, with no single gene, environmental factor, or pathological hallmark demonstrated to be both necessary and sufficient for disease onset and progression [ 10 , 26 , 27 , 28 , 29 , 30 ]. Significant variations in incidence across populations, including a relative absence in indigenous and hunter-gatherer societies, also suggests that there are sets of environmental exposures that are required to express the AD phenotype even in the setting of high genetic risk [ 31 , 32 , 33 ]. In fact, the case appears quite clear that the pathways underlying familial early-onset AD and ARD must now be considered separately, with decreasing weight being placed on the amyloid cascade in ARD and a greater appreciation of other upstream factors [ 5 ].…”

“…Indeed, although ApoE is the most well-known genetic determinant of ARD, no single genetic polymorphism is either necessary or sufficient to drive the development of ARCD. The critical moderating effect of the environment is perhaps best displayed in non-Westernized populations, some of which have shown either no effect of ApoE4 on ARD incidence, or a protective effect against ARCD in certain scenarios such as chronic parasitic infection [ 31 , 32 , 33 ].…”