Genome-wide association study of the rate of cognitive decline in Alzheimer's disease

Richard Sherva, Yorghos Tripodis, David A. Bennett, Lori B. Chibnik, Paul K. Crane, Philip L. De Jager, Lindsay A. Farrer, Andrew J. Saykin, Joshua M. Shulman, Adam Naj, Robert C. Green

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Background: Substantial interindividual variability exists in the disease trajectories of Alzheimer's disease (AD) patients. Some decline rapidly whereas others decline slowly, and there are no known explanations for this variability. We describe the first genome-wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition. Methods: The discovery sample was 303 AD cases recruited in the Alzheimer's Disease Neuroimaging Initiative and the replication sample was 323 AD cases from the Religious Orders Study and Rush Memory and Aging Project. In the discovery sample, Alzheimer's Disease Assessment Scale-cognitive subscale responses were tested for association with genome-wide single-nucleotide polymorphism (SNP) data using linear regression. We tested the 65 most significant SNPs from the discovery sample for association in the replication sample. Results: We identified SNPs in the spondin 1 gene (SPON1), the minor alleles of which were significantly associated with a slower rate of decline (rs11023139, P = 7.0 × 10-11) in the discovery sample. A SPON1 SNP 5.5 kb upstream was associated with decline in the replication sample (rs11606345, P =.002). Conclusion: SPON1 has not been previously associated with AD risk, but is plausibly related because the gene product binds to the amyloid precursor protein and inhibits its cleavage by β-secretase. These data suggest that SPON1 may be associated with the differential rate of cognitive decline in AD.

Original languageEnglish (US)
Pages (from-to)45-52
Number of pages8
JournalAlzheimer's and Dementia
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2014

Keywords

  • Alzheimer's disease
  • Cognitive decline
  • GWAS

ASJC Scopus subject areas

  • Health Policy
  • Epidemiology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Developmental Neuroscience
  • Clinical Neurology

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