Candidate gene analysis for Alzheimer's disease in adults with Down syndrome

Joseph H. Lee, Annie J. Lee, Lam Ha Dang, Deborah Pang, Sergey Kisselev, Sharon J. Krinsky-McHale, Warren B. Zigman, José A. Luchsinger, Wayne Silverman, Benjamin Tycko, Lorraine N. Clark, Nicole Schupf

Research output: Contribution to journalArticle

Abstract

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid β levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5–2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules.

Original languageEnglish (US)
Pages (from-to)150-158
Number of pages9
JournalNeurobiology of aging
Volume56
DOIs
StatePublished - Aug 2017

Keywords

  • APP
  • Alzheimer disease
  • CST3
  • Candidate genes
  • Dementia
  • Down syndrome
  • Gene mapping
  • MARK4

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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  • Cite this

    Lee, J. H., Lee, A. J., Dang, L. H., Pang, D., Kisselev, S., Krinsky-McHale, S. J., Zigman, W. B., Luchsinger, J. A., Silverman, W., Tycko, B., Clark, L. N., & Schupf, N. (2017). Candidate gene analysis for Alzheimer's disease in adults with Down syndrome. Neurobiology of aging, 56, 150-158. https://doi.org/10.1016/j.neurobiolaging.2017.04.018