The Effects of APOE and ABCA7 on Cognitive Function and Alzheimer’s Disease Risk in African Americans: A Focused Mini Review

Abstract

African Americans have double the prevalence of Alzheimer’s disease (AD), as compared to European Americans. However, the underlying causes of this health disparity are due to a multitude of environmental, lifestyle, and genetic factors that are not yet fully understood. Here, we review the effects of the two largest genetic risk factors for AD in African Americans: Apolipoprotein E (APOE) and ABCA7. We will describe the direct effects of genetic variation on neural correlates of cognitive function and report the indirect modulating effects of genetic variation on modifiable AD risk factors, such as aerobic fitness. As a means of integrating previous findings, we present a novel schematic diagram to illustrate the many factors that contribute to AD risk and impaired cognitive function in older African Americans. Finally, we discuss areas that require further inquiry, and stress the importance of racially diverse and representative study populations.

Commentary: APOE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort

“…Kuo and colleagues help to shed light on the association between APOE ε 4 and severe COVID-19 infection, and establish a starting point from which to initiate empirical and replicable studies aimed at investigating the molecular nature of such genetic risks. Indeed, these findings encourage comprehensive interpretations of population-specific susceptibilities to COVID-19 like those observed among African Americans ( 18 ), and the role that variation in APOE allele frequency may play ( 19 ). Their work also provides an important foundation from which to explore the biological mechanisms that underlie these associations.…”

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

“…Polymorphism associated with AD (Sun et al, 2005), decreased expression associated with increased risk (Lin et al, 2015) APOC4 [19 (50)] A lipid-binding lipoprotein thought to play a role in lipid metabolism Decreased expression associated with increased risk (Lin et al, 2015) ABCA7 [19 (1)] Member of the ATP-binding cassette (ABC) superfamily of transporters; catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of the membrane coupled with ATP hydrolysis, lipid homeostasis, binds APOA1, apolipoprotein-mediated phospholipid efflux from cells, cholesterol efflux, lipid raft organization Polymorphism correlate with memory impairment (Chang et al, 2019), amyloid plaque burden (Zhao Q. F. et al, 2015), cognitive impairment (Chung et al, 2014;Berg et al, 2019) ABCA1 [9 (107)] A membrane of the superfamily of ATP-binding cassette (ABC) transporters with cholesterol as its substrate, it functions as a cholesterol efflux pump in the cellular lipid removal pathway Polymorphism in AD (Chu et al, 2007;Wavrant-De Vrieze et al, 2007;Wang et al, 2013), modulates cholesterol efflux (Shibata et al, 2006;Khalil et al, 2012;Marchi et al, 2019), influences age of onset (Wollmer et al, 2003a) ABCA12 Cholesterol efflux (Hirsch-Reinshagen and Wellington, 2007;Wollmer et al, 2007;Marchi et al, 2019) LIPG [18 (43)] Diverse class of lipase enzymes includes diacylglycerol lipase (DAGL) and lipoprotein lipase (LPL) and endothelial lipase (LIPG). Hydrolyzes HDL more efficiently than other lipoproteins Polymorphism and mutation (Baum et al, 1999;Blain et al, 2006), cholesterol homeostasis (Blain and Poirier, 2004;Fidani et al, 2004), stimulation in nucleus basalis and hippocampus (Farooqui et al, 1988) (Continued) (Knebl et al, 1994;Demeester et al, 2000) SLC27A4 [9 (130)] Family of fatty acid transport proteins; translocation of long-chain fatty acids across the plasma membrane, has acyl-CoA ligase activity for long-chain and very-long-chain fatty acids (VLCFAs) SNP with p < 0.001 and significantly enriched in AD (Jones et al, 2010) NPC1 [18 (19...…”

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

“…However, many other SNPs in diverse genes may contribute to AD-related neurodegeneration and premature neuronal death, including genes encoding components of the pharmacogenetic machinery. Polymorphic variants in ABC and SLC transporters may affect AD pathogenesis and response to drugs [3,63,[68][69][70][71][72][73]. SNPs in genes encoding transporter proteins may affect brain penetrance and accessibility to neuronal/glial targets, drug metabolism, and drug resistance [70,74,75].…”