Genetic reports abstractA genome-wide scan for common variants affecting the rate of age-related cognitive decline
Introduction
Decline in cognitive performance occurs with advancing age and is associated with a variety of common, age-related chronic medical conditions. Alzheimer's disease (AD) is the most prevalent cause of dementia (Reitz et al., 2011a); however, many other common adult illnesses, including type 2 diabetes (Croxson and Jagger, 1995, Grodstein et al., 2001, Reijmer et al., 2010), cerebrovascular disease (Desmond et al., 2000, Pendlebury and Rothwell, 2009), as well as other cardiovascular risk factors (Desmond et al., 1993, Warsch and Wright, 2010), and inflammatory disorders (Lucin and Wyss-Coray, 2009) have been implicated in age-related cognitive decline. Based on autopsy series from community-based cohorts, most individuals with dementia have multiple contributory pathologies at the time of death (Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study, 2001, Sonnen et al., 2007, Troncoso et al., 2008). It is likely that diverse forms of brain injury interact to accelerate cognitive decline. For example, it has been suggested that vascular-related brain injury may promote the development of AD pathology or, less directly, the clinical manifestation of AD-related cognitive decline (Launer et al., 2008, Schneider and Bennett, 2010, Warsch and Wright, 2010). Results from a variety of experimental paradigms for the study of neuronal injury and repair indicate that overlapping cellular and molecular mechanisms likely mediate the response to a diversity of central nervous system insults (Bishop et al., 2010, Cho et al., 2010; Lucin and Wyss-Coray, 2009, Martinez-Vicente and Cuervo, 2007, Ross and Poirier, 2004). Besides the local reactions to brain lesions, the ability of neuronal networks to adapt to and compensate for an accumulated burden of injury, sometimes referred to as cognitive reserve (Stern, 2009), likely has a substantial impact on the trajectory of cognitive decline. Studies of elder twins suggest substantial heritability in cognitive performance in late life (McClearn et al., 1997, Swan et al., 1990), and we hypothesize that a core genetic network might therefore impact susceptibility for rate of age-related cognitive decline.
Genome-wide association studies have proven a successful strategy for discovering susceptibility genes for complex human traits, including neurologic disorders, such as AD (Bertram and Tanzi, 2009). Besides the apolipoprotein E locus (APOE), these studies have identified common variants in ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A4/MS4A6E, and PICALM as associated with AD susceptibility (Harold et al., 2009, Hollingworth et al., 2011; Lambert et al., 2009, Naj et al., 2011, Seshadri et al., 2010). While elucidating the functional impact of disease-associated genetic variants remains an active area of investigation, there is evidence that these genes may have important roles beyond AD pathogenesis in affecting other disorders potentially relevant to cognitive decline. For example, in addition to the well-known effect of the APOE locus in promoting AD risk, this locus has also been associated with dyslipidemia, cardiovascular disease, and increased cerebral infarcts (Eichner et al., 2002, Kim et al., 2003, McCarron et al., 1999). Similarly, polymorphisms in the CR1 gene, encoding a complement receptor, have previously been associated with susceptibility for infectious disease, particularly malaria (Cockburn et al., 2004, Rowe et al., 1997). We have shown that polymorphisms in both APOE (Wilson et al., 2002a, Wilson et al., 2002b) and CR1 (Chibnik et al., 2011) have a measurable impact on age-related cognitive decline, including in subjects without dementia, and further, that these associations are mediated in part by an effect on promoting amyloid plaque pathology (Bennett et al., 2005a, Chibnik et al., 2011).
The Religious Orders Study (ROS) is following more than 1100 older Catholic nuns, priests, and brothers who have completed up to 16 years of annual cognitive testing. Here, we have leveraged available genotyping data for 749 subjects of European ancestry with longitudinal cognitive data to conduct a genome scan for loci associated with the rate of age-related cognitive decline. We report efforts to replicate the best results using data from 2 complementary, community-based studies, the Rush Memory and Aging Project (MAP) and Chicago Health and Aging Project (CHAP), as well as a predominantly clinic-derived subject sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI), and offer evidence in support of replication for 1 variant. Finally, we explore whether known genetic susceptibility factors associated with other illnesses that are known to influence the risk of dementia, such as AD, cardiovascular disease, and type 2 diabetes, also affect age-related cognitive decline.
Section snippets
Subjects
Subjects are participants from 4 longitudinal studies, which are each described below. The number of study subjects with genotyping data, included in the genetic analyses, are described in the Genotyping Methods subsection, and also summarized in Table 1.
The ROS, started in 1994, enrolls Catholic priests, nuns, and brothers, aged 53 or older from about 40 groups in 12 states. Since January 1994, 1132 participants completed their baseline evaluation, of whom 1001 are non-Hispanic white, and the
Characteristics of the discovery cohort
Following quality control, genome-wide genotype data (672,266 SNPs) were available on 749 non-Hispanic, white subjects from the ROS with longitudinal cognitive testing. Detailed cohort characteristics are presented in Table 1. The mean age at enrollment was 75 years, and subjects were followed for 9 years, on average (range 1–15 years of follow-up). Cognitive decline trajectories were quantified based on annual performance of 17 distinct neuropsychological tests sampling 5 cognitive domains
Discussion
We report the results of a genome-wide scan in 749 elder subjects to identify loci associated with the rate of cognitive decline, using a mixed effects model that incorporates repeated cognitive measures. Consistent with numerous prior studies (Feskens et al., 1994; Haan et al., 1999, Henderson et al., 1995; Hyman et al., 1996, Jonker et al., 1998, Wilson et al., 2002a, Wilson et al., 2002b), we found robust evidence for association between the APOE locus and the rate of age-related cognitive
Disclosure statement
The authors have no conflicts of interest to report related to this work.
Acknowledgements
The authors thank Sara Pulit for help with assembling a comprehensive list of SNPs associated with inflammatory diseases. The authors are also grateful to the participants in the Religious Orders Study, the Chicago Health and Aging Project, the Memory and Aging Project, and the Alzheimer's Disease Neuroimaging Initiative. This work is supported by the National Institutes of Health [R01 AG030146, P30 AG10161, R01 AG17917, R01 AG15819, K08 AG034290, P30 AG10161 and R01 AG11101], and the Illinois
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Contributed equally to this study.