Genetic studies on late-onset Alzheimer's disease (AD) have repeatedly mapped susceptibility loci onto chromosome 12q13, encompassing the vitamin D receptor (VDR) gene. Epidemiology studies have indicated vitamin D insufficiency as a risk factor for AD. Given that VDR is the major mediator for vitamin D's actions, we sought to clarify the role of VDR in late-onset AD. We conducted an association study in 492 late-onset AD cases and 496 controls with 80 tagging single nucleotide polymorphisms (SNPs). The strongest association was found at a promoter SNP rs11568820 (P = 9.1×10−6, odds ratio (OR) = 1.69), which resides within the transcription factor Cdx-2 binding site and the SNP has been also known as CDX2. The risk-allele at rs11568820 is associated with lower VDR promoter activity (p < 10−11). The overexpression of VDR or vitamin D treatment suppressed amyloid precursor protein (APP) transcription in neuroblastoma cells (p < 0.001). We provide both statistical evidence and functional data suggesting VDR confers genetic risk for AD. Our findings are consistent with epidemiology studies suggesting that vitamin D insufficiency increases the risk of developing AD.
Late-onset Alzheimer's disease (Alzheimer's disease (AD) [MIM 104300]) is a progressive neurodegenerative disorder with environmental and genetic components. For familial, early-onset AD, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) have been identified as causal genes. For late-onset AD, apolipoprotein E (APOE) gene has been universally established as a susceptibility gene (Corder et al., 1993, Farrer et al., 1997 and Saunders et al., 1993). However, 50% of late-onset AD patients do not carry the APOEε4 allele, indicating the existence of additional genetic factors for late-onset AD (Daw et al., 2000 and Slooter et al., 1998).
In searching for additional genetic risk factors for late-onset AD, our group first reported strong evidence for linkage on chromosome 12q13 (Pericak-Vance et al., 1997), which was replicated by multiple independent studies (Kehoe et al., 1999, Rogaeva et al., 1998 and Wu et al., 1998). The vitamin D receptor (VDR) gene, located within the critical interval on 12q13, is a plausible candidate to confer susceptibility for late-onset AD. As the receptor for 1,25-dihydroxy vitamin D3 (1,25-(OH)2 D3, the active metabolite of vitamin D), VDR mediates biological actions of vitamin D. It has been increasingly recognized that vitamin D is involved in not only Ca2+ homeostasis in bone but also plays an active role in the nervous system (Garcion et al., 2002). First, enzymes involved in 1,25-(OH)2 D3 biosynthesis and degradation have been found in the brain (Neveu et al., 1994 and Zehnder et al., 2001). The VDR is expressed in the human brain, with the highest expression in the hypothalamus and in the large neurons of the substantia nigra (Eyles et al., 2005 and Sutherland et al., 1992). Second, cross-sectional studies have reported higher prevalence of vitamin D deficiency in AD patients and individuals with vitamin D insufficiency (25 dihydroxy vitamin D3 ≤ 20 ng/mL) had double the risk of having AD comparing to individuals with sufficient vitamin D status (Buell et al., 2010 and Sato et al., 1998). Furthermore, vitamin D deficiency has been found to be associated with cognitive impairment in both AD patients and general population (Annweiler et al., 2010, Oudshoorn et al., 2008, Przybelski and Binkley, 2007 and Wilkins et al., 2006). Recently, in a prospective study of more than 1000 elderly men, a lower serum vitamin D level at baseline predicates cognitive decline during the 4.6 years follow-up (Slinin et al., 2010). Interestingly, our recent genome-wide association study (GWAS) on late-onset AD detected evidence for association in VDR (p = 0.0006–0.0001) ( Beecham et al., 2009).
Alzheimer's disease is characterized by the presence of cerebral senile plaques composed of aggregated amyloid-β (Aβ) peptides produced from proteolytic cleavage of the APP. It is generally thought that APP plays a key role in the pathogenesis of AD (Hardy and Selkoe, 2002). Missense mutations in the APP gene were the first genetic factor identified for familial early-onset AD (Chartier-Harlin et al., 1991 and Tanzi et al., 1992). The gene dosage of APP is known to be crucial for AD pathogenesis. Down syndrome or trisomy 21 caused by the presence of all or part of an extra chromosome 21 shows AD brain pathology (Wisniewski et al., 1985). Recently, it has been reported that APP duplication causes autosomal dominant early-onset AD (Rovelet-Lecrux et al., 2006). As a transcription factor, VDR interacts with SMAD3 (Yanagisawa et al., 1999) which is known to regulate APP transcription through TGF beta signaling (Lesné et al., 2003). It is intuitive to postulate that VDR confers genetic susceptibility to AD via modulating APP transcription.
