ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer’s disease

• Published in: Neurobiology of aging 2003-05, Vol.24 (3), p.421-426
• Main Authors: Wollmer, M.Axel, Streffer, Johannes R, Lütjohann, Dieter, Tsolaki, Magdalini, Iakovidou, Vassiliki, Hegi, Thomas, Pasch, Thomas, Jung, Hans H, Bergmann, Klaus von, Nitsch, Roger M, Hock, Christoph, Papassotiropoulos, Andreas
• Format: Article
• Language: English
• Subjects: Age of Onset; Aged; Alzheimer Disease - epidemiology; Alzheimer Disease - genetics; Amyloid beta-Peptides - analysis; Amyloid beta-Peptides - genetics; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Case-Control Studies; Cholesterol - cerebrospinal fluid; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Genetic association; Greece - epidemiology; Humans; Male; Medical sciences; Middle Aged; Neurology; Polymorphism, Genetic; Risk Factors; Single nucleotide polymorphism; Switzerland - epidemiology; β-Amyloid
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/S0197-4580(02)00094-5

Increased formation of the β-amyloid peptide (Aβ) is a central event in the pathogenesis of Alzheimer’s disease (AD). High cellular cholesterol load promotes Aβ formation. The ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux from cells. We hypothesized that genetic variability in ABCA1 may influence cholesterol metabolism in the central nervous system (CNS) and, thus, interfere with the development of AD. Healthy elderly carriers of the A allele of a non-synonymous (R219K) single nucleotide polymorphism (SNP) in the ABCA1 gene (rs2234884) had on average 33% lower total cholesterol in cerebrospinal fluid (CSF) than non-carriers. In 169 patients with late onset, sporadic AD, this allele was associated with delayed age at onset of the disease by 1.7 years on average. Rs2234884 and another non-synonymous SNP (R1587K) in ABCA1 (rs2234886) failed to show significant association with the risk for AD. We conclude that genetic variability of ABCA1 influences the development of AD, possibly by interfering with CNS cholesterol homeostasis.