It is known that individuals with Down syndrome develop Alzheimer’s disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer’s disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer’s disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer’s disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer’s disease in Down syndrome.
Down syndrome (DS), also referred to as trisomy 21, is caused by an extra copy of chromosome 21. Occurring in approximately 1 in 800 live births, it is the most common chromosomal abnormality resulting in learning difficulties.
The prevalence of Alzheimer's disease (AD) in people with DS increases significantly with age, and dementia in people with DS is one of the most common forms of dementia among individuals under the age of 50 years. Despite the occurrence of AD pathology, including amyloid plaques and neurofibrillary tangles, in the brains of individuals with DS as young as 40 years (Wisniewski et al., 1994), the age at onset (AAO) of AD can vary widely. The mean AAO of dementia is 50 to 55 years (Prasher and Krishnan, 1993), with a range from 38 to 70 years.
The early-onset AD that occurs in people with DS is thought to be largely due to the triplication of APP, which is located on chromosome 21. Indeed, APP duplications have been shown to cause early-onset AD in the disomic population ( McNaughton et al., 2012; Rovelet-Lecrux et al., 2006; Sleegers et al., 2006), although these are not always fully penetrant ( Hooli et al., 2012).
As dementia in the DS population can develop over a range of ages, it is likely that, as with sporadic AD in the general population, genetic factors play a major role. Although mutations in a small number of genes associated with the production of amyloid, such as APP, PSEN1, and PSEN2, have been found to cause early-onset AD in the general population, the majority of AD cases are sporadic and are likely to have a complex genetic etiology. APOE is a key genetic risk factor for late-onset AD in the general population ( Corder et al., 1993), and large genome-wide association studies (GWAS) carried out in recent years have identified further risk genes: CLU, PICALM, BIN1, CR1, ABCA7, CD2AP, EPHA1, CD33, and the MS4 locus ( Harold et al., 2009; Hollingworth et al., 2011; Naj et al., 2011; Seshadri et al., 2010). Although we and others have shown APOE to affect AD risk in DS individuals ( Deb et al., 2000; Prasher et al., 2008; Royston et al., 1996), this result has not been replicated in all studies ( Margallo-Lana et al., 2004; van Gool et al., 1995).
A study by Patel et al. (2011) examined SNPs in 28 genes associated with AD risk, selected from literature published up until March 2008. Five genes including APOE were associated with AD risk.
No therapies have specifically been developed for the treatment of AD in DS, and, as the life expectancy of people with DS is increasing, it is becoming more important to understand the factors affecting age-related diseases in this population (Coppus et al., 2006; Holland et al., 2000).
Given the almost universal presence of early-onset AD pathology in people with DS, factors affecting AAO, severity, and disease progression need closer analysis. This may also provide information relevant to those at risk of developing AD in the general population. In this study, we examined the impact of SNPs that have recently been associated with AD risk in the general population, in 2 large meta-analyses (Hollingworth et al., 2011; Naj et al., 2011), upon AAO of AD in people with DS.
