Ethnicity‐dependent genetic association of ABCA2 with sporadic Alzheimer's disease

Abstract

A recent study demonstrated a significant genetic association between the ATP-binding cassette transporter A2 (ABCA2) and the risk for Alzheimer's disease (AD) in a large Caucasian sample. The rare T allele of the synonymous exonic single nucleotide polymorphism (SNP) rs908832 was overrepresented in early-onset AD patients as compared to cognitively healthy controls. Here we confirm the association of rs908832 with AD in a Western European population (n = 291, P = 0.008). In a second sample from Southern Europe, rs908832 was not associated with AD. Interestingly, rs908832 was not polymorphic in a Japanese sample. Furthermore, rs908832 was not associated with either serum cholesterol levels or with the risk for coronary artery disease, but seemed to be related to cholesterol levels in the cerebrospinal fluid. These data suggest that ABCA2 may exert population-dependent effects on the genetic risk for sporadic AD and support a role of ABC lipid transporters in the pathogenesis of this disease.

Down-regulation of the ATP-binding Cassette Transporter 2 (Abca2) Reduces Amyloid-β Production by Altering Nicastrin Maturation and Intracellular Localization

“…This led us to use genetic tools to investigate how cholesterol dyshomeostasis may lead to AD. We focused our attention on the ATP-binding cassette transporter-2 (Abca2) for two reasons: (i) Abca2 has been genetically linked to Alzheimer disease (22,23) and (ii) Abca2 plays a role in intracellular sterol trafficking (24).…”

“…The endosomal-lysosomal pathway is also known to be the major site of A␤ generation (33)(34)(35) and further studies demonstrated a co-localization of Abca2 and APP in intracellular vesicles of neuroblastoma cells (36). The clinical relevance of Abca2 is suggested by two independent studies that strongly linked the identical single nucleotide polymorphism to AD (22,23). However, the underlying molecular mechanism is still unclear.…”

“Skittish” Abca2 Knockout Mice Display Tremor, Hyperactivity, and Abnormal Myelin Ultrastructure in the Central Nervous System

“…AD predisposition is associated, albeit controversially, with circulating and cerebrospinal fluid (CSF) cholesterol levels and linkage to cholesterol homeostasis genes, including the APOE e4, CYP46A1, and ABCA1 genes (40). Recently, a single-nucleotide polymorphism within exon 14 of Abca2 (rs908832) was linked to earlyonset AD (26,43). This mutation produces elevated cholesterol levels in CSF, a risk factor for AD (43).…”

“…Recently, a single-nucleotide polymorphism within exon 14 of Abca2 (rs908832) was linked to earlyonset AD (26,43). This mutation produces elevated cholesterol levels in CSF, a risk factor for AD (43). The effects on CSF cholesterol and AD age of onset are shared by mutants of Abca1, the closest relative of Abca2; both are cholesterolresponsive genes with identity in a C-terminal region (VFVNFA) associated with the ABCA1-apoA1 interaction and lipid efflux (11,19).…”

The ABCA2 Transporter: Intracellular Roles in Trafficking and Metabolism of LDL-Derived Cholesterol and Sterol-Related Compounds

“…ABCA2 levels were shown to be elevated in the temporal and frontal regions of the brain, areas frequently associated with AD pathology. Recently, a synonymous SNP in exon 14 of ABCA2 (rs908832) was determined to have a significant linkage with early-onset AD [80,81] and an impact on cholesterol in cerebrospinal fluid [81]. This transporter was also shown to localize in specific areas of the brain associated with adult neurogenesis and AD pathology (subventricular zone lining of the lateral ventricles and the dentate gyrus of the hippocampus) and in GABAergic and glutamatergic neurons [82].…”