The role of ECE1 variants in cognitive ability in old age and Alzheimer's disease risk

Gillian Hamilton, Sarah E Harris, Gail Davies, David C Liewald, Albert Tenesa, Antony Payton, Michael A Horan, William E R Ollier, Neil Pendleton, John M Starr, David Porteous, Ian J Deary, Genetic and Environmental Risk for Alzheimer's Disease (GERAD1) Consortium, Patrick Kehoe

Research output: Contribution to journalArticle (Academic Journal)peer-review

10 Citations (Scopus)


The β-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aβ-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in individuals that carried at least one APOE ε4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in individuals lacking the APOE ε4 allele (P = 0.00036, β = -0.19). Both results showed a trend towards significance after permutation (0.05 < P < 0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z < 0.05) of SNPs in the ECE-1b promoter with non-verbal reasoning scores, particularly in individuals lacking the APOE ε4 allele. Our genetic findings are not wholly consistent. Nonetheless, the AD associated intronic haplotype is linked to the 338A variant of known ECE1b promoter variant, 338C>A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.

Original languageEnglish
Pages (from-to)696-709
Number of pages14
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Issue number6
Publication statusPublished - Sept 2012

Bibliographical note

Copyright © 2012 Wiley Periodicals, Inc.

Structured keywords

  • Dementia Research Group


  • Aged
  • Aging
  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Aspartic Acid Endopeptidases
  • Cognition
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Meta-Analysis as Topic
  • Metalloendopeptidases
  • Middle Aged
  • Neuropsychological Tests
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Proteolysis
  • Risk Factors


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