Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with Down syndrome

Constance Chace, Deborah Pang, Catherine Weng, Alexis Temkin, Simon Lax, Wayne Silverman, Warren Zigman, Michel Ferin, Joseph H. Lee, Benjamin Tycko, Nicole Schupf

Research output: Contribution to journalArticle

Abstract

CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.

Original languageEnglish (US)
Pages (from-to)601-612
Number of pages12
JournalJournal of Alzheimer's Disease
Volume28
Issue number3
DOIs
StatePublished - 2012

Keywords

  • Alzheimer's disease
  • CYP17
  • CYP19
  • Down syndrome
  • aromatase
  • estrogen
  • genetics

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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    Chace, C., Pang, D., Weng, C., Temkin, A., Lax, S., Silverman, W., Zigman, W., Ferin, M., Lee, J. H., Tycko, B., & Schupf, N. (2012). Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with Down syndrome. Journal of Alzheimer's Disease, 28(3), 601-612. https://doi.org/10.3233/JAD-2011-110860