ABCA7, a Genetic Risk Factor Associated with Alzheimer’s Disease Risk in African Americans

Article type: Review Article

Authors: Stepler, Kaitlyn E.^a | Gillyard, Taneisha R.^b | Reed, Calla B.^a | Avery, Tyra M.^c | Davis, Jamaine S.^{b; e; *} | Robinson, Renã A.S.^{a; d; e; f; g; *}

Affiliations: [a] Department of Chemistry, Vanderbilt University, Nashville, TN, USA | [b] Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, USA | [c] Department of Life and Physical Sciences, Fisk University, Nashville, TN, USA | [d] Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA | [e] Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA | [f] Vanderbilt Institute of Chemical Biology, Nashville, TN, USA | [g] Vanderbilt Brain Institute, Nashville, TN, USA

Correspondence: [*] Correspondence to: Prof. Jamaine S. Davis, PhD, Department of Biochemistry & Cancer Biology, School of Medicine, Meharry Medical College, 1023 21st Avenue N, 2007 WBS Bldg Nashville, TN 37208, USA. Tel.: +1 615 963 2847; E-mail: [email protected] and Prof. Renã A.S. Robinson, PhD, Department of Chemistry, Vanderbilt University, 5423 Stevenson Center, Nashville, TN 37235, USA. Tel.: +1 615 343 0129; [email protected].

Abstract: African American/Black adults are twice as likely to have Alzheimer’s disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE) ɛ4 allele in African American/Black adults. ABCA7 is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and ‘omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted.

Keywords: African Americans, Alzheimer’s disease, Blacks, health status disparities, human ABCA7 protein, proteomics, single nucleotide polymorphism, subfamily A of ATP binding cassette transporter

DOI: 10.3233/JAD-215306

Journal: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 5-19, 2022