The effect of APOE genotype on Alzheimer's disease risk is influenced by sex and docosahexaenoic acid status

Abstract

An apolipoprotein E ε4 (APOE-ε4) genotype is the strongest common genetic determinant of Alzheimer's disease (AD). The pleiotropic nature of apolipoprotein E has made elucidation of the aetiological basis difficult to establish, which is further complicated by the fact that the penetrance of the APOE-ε4 allele is modulated by sex, age, and nutrition. A greater metabolic consequence of the APOE-ε4 allele is likely to contribute to the fact that two-thirds of AD patients are female. A higher tissue status of the marine n-3 fatty acid docosahexaenoic acid (DHA) is associated with a lower AD risk. However, APOE-ε4 carriers appear less sensitive to the neurocognitive benefits, which may be due to defective blood-brain barrier transport of DHA exacerbated by aging and possibly sex. This suggests higher DHA requirements in this large population subgroup. This narrative review will consider the influence of sex and DHA in modulating APOE-ε4–mediated AD risk.

Introduction

Dementias, of which Alzheimer's disease (AD) is the most common, are complex multifactorial disorders that manifest progressively over time, with deleterious behaviors and genetic predisposition contributing to compromised cognitive function. The apolipoprotein E ε4 (APOE-ε4) allele is the strongest prevalent genetic risk factor for sporadic late-onset AD with possession of 1 or 2 APOE-ε4 conferring 3- to 4- and 8- to 12-fold increased risk, respectively, and reduced age of onset (Davidson et al., 2007, Heffernan et al., 2016). While a significant risk factor, possession of an APOE-ε4 does not categorically determine AD outcome (Corder et al., 1993, Liu et al., 2013). APOE-ε4 prevalence within global AD populations varies considerably ranging from 41% to 61% (Corbo and Scacchi, 1999, Crean et al., 2011, Farrer et al., 1997) and only half of APOE-ε4 homozygotes develop AD by age 90 years (Henderson et al., 1995). This indicates that the penetrance of the ε4 allele, its influence on the rate of cognitive decline and the likelihood of transitioning to mild cognitive impairment (MCI) and AD, is variable and potentially modifiable (Fenesi et al., 2017, Moser and Pike, 2017, Singh et al., 2006, Ward et al., 2012).

Because of the pleiotropic nature of apolipoprotein E (apoE), possession of the deleterious APOE-ε4 allele influences multiple biological processes, including inflammation, amyloid beta deposition, neurogenesis, synaptic function, and lipid metabolism (including cholesterol and docosahexaenoic acid [DHA]) (Alata et al., 2015, Holtzman et al., 2012, Huang and Mahley, 2014, Theendakara et al., 2016). Originally described for its role in lipid transport, in contrast to the systemic circulation, apoE is the almost exclusive lipid transporter within the central nervous system (Bu, 2012).

Regular consumption of long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), eicosapentaenoic acid, and DHA, found in high concentrations in oily fish is associated with reduced AD risk (Barberger-Gateau et al., 2007, Zhang et al., 2016). Current evidence suggests that the cognitive responsiveness to DHA intake is lower in APOE-ε4 individuals (Childs et al., 2014, Davis et al., 2017, Kofler et al., 2012, Metherel et al., 2009, Minihane, 2016, Slim et al., 2017, Walker et al., 2014).

Furthermore, the pathological impact of APOE-ε4 carrier status appears to be modified by sex, with female carriers found to have increased MCI or AD risk between the ages of 55 and 70 years compared to their male counterparts (Farrer et al., 1997, Neu et al., 2017), suggesting a possible role of menopausal transition.

Therefore, those with an APOE-ε4 genotype, particularly postmenopausal females, are a large “at-risk” population group who should be targeted for preventive intervention, such as LC n-3 PUFA supplementation. Strategies capable of delaying disease onset by as little as 2 years would have profound implications on current disease burden (Brookmeyer et al., 1998). Recent predictive UK models suggest that achieving a 2- or 5-year delay would result in a respective 19% or 33% reduction in the predicted AD prevalence by 2050 (Lewis et al, 2014) and alleviate the social and economic pressures associated with this debilitating disease.

This review will consolidate the current evidence of the interactive role of APOE genotype, DHA status and sex in the development of AD, highlighting research gaps and directions for future investigation.