Elsevier

Neurobiology of Aging

Volume 33, Issue 5, May 2012, Pages 1017.e1-1017.e15
Neurobiology of Aging

Genetic reports abstract
A genome-wide scan for common variants affecting the rate of age-related cognitive decline

https://doi.org/10.1016/j.neurobiolaging.2011.09.033Get rights and content

Abstract

Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (PDISC = 5.6 × 10−9; PJOINT = 3.7 × 10−27). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (PDISC = 6.7 × 10−5; PREP = 9.4 × 10−3; PJOINT = 2.3 × 10−5). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.

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

References (81)

  • S. Pérez-Torres et al.

    Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer's disease brains examined by in situ hybridization

    Exp. Neurol.

    (2003)
  • S. Purcell et al.

    PLINK: a tool set for whole-genome association and population-based linkage analyses

    Am. J. Hum. Genet.

    (2007)
  • Y. Stern

    Cognitive reserve

    Neuropsychologia

    (2009)
  • Z. Arvanitakis et al.

    Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function

    Arch. Neurol.

    (2004)
  • J.C. Barrett et al.

    Haploview: analysis and visualization of LD and haplotype maps

    Bioinformatics

    (2005)
  • D. Bennett et al.

    Neuropathology of older persons without cognitive impairment from two community-based studies

    Neurology

    (2006)
  • D. Bennett et al.

    Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people

    J. Neurol. Neurosurg. Psychiatry

    (2005)
  • D.A. Bennett et al.

    Decision rules guiding the clinical diagnosis of Alzheimer's disease in two community-based cohort studies compared to standard practice in a clinic-based cohort study

    Neuroepidemiology

    (2006)
  • D.A. Bennett et al.

    The Rush Memory and Aging Project: study design and baseline characteristics of the study cohort

    Neuroepidemiology

    (2005)
  • D.A. Bennett et al.

    Natural history of mild cognitive impairment in older persons

    Neurology

    (2002)
  • L. Bertram et al.

    Genome-wide association studies in Alzheimer's disease

    Hum. Mol. Genet.

    (2009)
  • J.L. Bienias et al.

    Design of the Chicago Health and Aging Project (CHAP)

    J. Alzheimers Dis.

    (2003)
  • A. Biffi et al.

    Genetic variation and neuroimaging measures in Alzheimer disease

    Arch. Neurol.

    (2010)
  • N.A. Bishop et al.

    Neural mechanisms of ageing and cognitive decline

    Nature

    (2010)
  • L.B. Chibnik et al.

    CR1 is associated with amyloid plaque burden and age-related cognitive decline

    Ann. Neurol.

    (2011)
  • D.H. Cho et al.

    Mitochondrial dynamics in cell death and neurodegeneration

    Cell. Mol. Life Sci.

    (2010)
  • I.A. Cockburn et al.

    A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • S.C. Croxson et al.

    Diabetes and cognitive impairment: a community-based study of elderly subjects

    Age Ageing

    (1995)
  • P. De Jager et al.

    Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

    Nat. Genet.

    (2009)
  • D.W. Desmond et al.

    Frequency and clinical determinants of dementia after ischemic stroke

    Neurology

    (2000)
  • D.W. Desmond et al.

    Risk factors for cerebrovascular disease as correlates of cognitive function in a stroke-free cohort

    Arch. Neurol.

    (1993)
  • J.E. Eichner et al.

    Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review

    Am. J. Epidemiol.

    (2002)
  • D.A. Evans et al.

    Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status

    Arch. Neurol.

    (2003)
  • E.J. Feskens et al.

    Apolipoprotein e4 allele and cognitive decline in elderly men

    BMJ

    (1994)
  • F. Grodstein et al.

    Type 2 diabetes and cognitive function in community-dwelling elderly women

    Diabetes Care

    (2001)
  • M.N. Haan et al.

    The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons

    JAMA

    (1999)
  • D. Harold et al.

    Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

    Nat. Genet.

    (2009)
  • P. Hollingworth et al.

    Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

    Nat. Genet.

    (2011)
  • B.T. Hyman et al.

    Apolipoprotein E and cognitive change in an elderly population

    Ann. Neurol.

    (1996)
  • K.A. Frazer et al.

    A second generation human haplotype map of over 3.1 million SNPs

    Nature

    (2007)
  • Cited by (46)

    • Genetic Evidence Supporting a Causal Role of Depression in Alzheimer's Disease

      2022, Biological Psychiatry
      Citation Excerpt :

      After quality control, there were 340,516 CpGs in 664 individuals for analysis (Table S1B in Supplement 2). Genotyping of ROS/MAP participants were profiled using either the Illumina OmniQuad Express, Affymetrix GeneChip 6.0, or whole-genome sequencing (23,28). Whole-genome sequencing was prioritized when multiple data sources were available.

    • The potential roles of genetic factors in predicting ageing-related cognitive change and Alzheimer's disease

      2021, Ageing Research Reviews
      Citation Excerpt :

      In elderly adults, it was reported that APOE- ε4 could contribute to more-rapid cognitive decline (Packard et al., 2007). By using a genome-wide scan approach, De Jager et al. found that APOE- ε4 was significantly associated with the rate of cognitive decline (p< 5 × 10−8) (De Jager et al., 2012). Furthermore, APOE- ε4 has been associated with reduced cognitive functions in older adults (Wisdom et al., 2011).

    • How 3', 5'-cyclic nucleotide phosphodiesterases change in the brain with normal aging and dementia

      2021, Factors Affecting Neurological Aging: Genetics, Neurology, Behavior, and Diet
    View all citing articles on Scopus
    1

    Contributed equally to this study.

    View full text