ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease
Introduction
Alzheimer's disease (AD) is the most common cause of dementia in the elderly and a major socioeconomic burden in our aging population. To date, four genes have been significantly associated with AD, which altogether account for less than 30% of the genetic variance for this disease, suggesting that additional genes remain to be identified. Numerous other candidate genes have been proposed but with various levels of statistical significance and replication (Bertram and Tanzi, 2004). Several epidemiological and biochemical studies have indicated a link between cholesterol and Alzheimer's disease (Casserly and Topol, 2004, Hartmann, 2001, Puglielli et al., 2003, Simons et al., 2001). A high serum cholesterol concentration during mid-life increases the prevalence of AD (Kivipelto et al., 2001) when conversely the use of some cholesterol-lowering drugs (statins) decreases the risk of developing AD (Jick et al., 2000, Wolozin et al., 2000). Recent in vivo and in vitro mechanistic studies also support this link. Cholesterol levels have been shown to correlate with levels of the β-amyloid peptide (Aβ), the main component of AD senile plaques and vascular deposits (Puglielli et al., 2001, Tanzi and Bertram, 2001). In vivo, treatments with statins and other hypocholesterolemic agents reduce Aβ levels (Fassbender et al., 2001, Refolo et al., 2001, Simons et al., 1998). Genetic studies have also indicated a link between cholesterol and AD. APOE, the main cholesterol carrier in the brain, is the most common genetic risk factor for AD (Saunders et al., 1993). CYP46A1 (the major catabolic pathway for brain cholesterol) polymorphisms have also been associated with AD (Papassotiropoulos et al., 2003). Although cholesterol metabolism in the brain remains poorly defined (Dietschy and Turley, 2001), it relies exclusively on local synthesis and transport between the glial and neuronal cellular pools. In the periphery, members of the ATP-binding cassette, sub-family A (ABC-A) transporters are known to participate in cholesterol and phopholipid transport (Smith et al., 2004). In particular, ABCA1 is mutated in Tangier's disease (Rust et al., 1999), which is characterized, in particular, by low HDL cholesterol levels and more recently a genetic association with AD has been identified and replicated (Wollmer et al., 2003, Katzov et al., 2004). The related human ABCA2 transporter is predominantly expressed in the brain, both in glial and neuronal cells (Schmitz and Kaminski, 2002, Vulevic et al., 2001). The ABCA2 gene has been identified as a cholesterol-responsive gene (Kaminski et al., 2001) and very recent data indicate that its expression can modulate Aβ production (Chen et al., 2004, Davis et al., 2004). ABCA2 is therefore a very plausible candidate gene for AD. We thus investigated whether genetic variation in ABCA2 was associated with Alzheimer's disease.
Section snippets
Participants
Our study included 440 unrelated AD cases and 519 controls. Within the control group, 45% of the individuals were male; they were 39% within the case group. Patients were recruited by a clinical network from consecutive admissions in several hospitals. All subjects were Caucasian of French origin. The AD patients were recruited by a clinical network from consecutive admissions in several hospitals. Patients fulfilled the NINCDS-ADRDA criteria for probable AD (McKahnn et al., 1984). Controls
Results
Seventeen kilobases of the 22.3 kb of the ABCA2 genomic sequence comprising the 48 exons, 41 of the 47 introns and 1 kb of 5′-flanking DNA sequence including the basal promoter (Davis et al., 2003) were fully sequenced on 150 individuals from our control sample and 102 SNPs were discovered. Due to their large size, six introns (number 1, 2, 5, 7, 9 and 47) were only partially sequenced. Finally, to have a comprehensive SNP coverage, searches in public and private databanks were made to find
Discussion
Starting from the recently suggested link between cholesterol and Alzheimer's disease, we tested for association with the disease, 45 SNPs of the ABCA2 gene. One synonymous SNP of the gene, located in exon 14, was found significantly associated with AD in two subsamples and additional analyses on the whole sample identified this SNP as a strong risk factor for the early-onset form of AD. The association test performed on the second subsample allows us to say that the significant association
Acknowledgments
We thank Martine Cano-Petit and Fabrice Herbin for support. The three SNPs located within introns 1, 2 and 9 were obtained from CELERA Genomics associated databases through the use of the CELERA Discovery System.
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These authors contributed equally to this work.