Olfactory copy number association with age at onset of Alzheimer disease

Neurology. 2011 Apr 12;76(15):1302-9. doi: 10.1212/WNL.0b013e3182166df5.


Objectives: Copy number variants (CNVs) have been recognized as a source of genetic variation that contributes to disease phenotypes. Alzheimer disease (AD) has high heritability for occurrence and age at onset (AAO). We performed a cases-only genome-wide CNV association study for age at onset of AD.

Methods: The discovery case series (n = 40 subjects with AD) was evaluated using array comparative genome hybridization (aCGH). A replication case series (n = 507 subjects with AD) was evaluated using Affymetrix array (n = 243) and multiplex ligation-dependent probe amplification (n = 264). Hazard models related onset age to CNV.

Results: The discovery sample identified a chromosomal segment on 14q11.2 (19.3-19.5 Mb, NCBI build 36, UCSC hg18 March 2006) as a region of interest (genome-wide adjusted p = 0.032) for association with AAO of AD. This region encompasses a cluster of olfactory receptors. The replication sample confirmed the association (p = 0.035). The association was found for each APOE4 gene dosage (0, 1, and 2).

Conclusion: High copy number in the olfactory receptor region on 14q11.2 is associated with younger age at onset of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Alzheimer Disease / epidemiology*
  • Alzheimer Disease / genetics*
  • Apolipoprotein E4 / genetics
  • Chromosome Mapping
  • Chromosomes, Human, Pair 14 / genetics
  • Cohort Studies
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations*
  • Gene Dosage
  • Humans
  • Proportional Hazards Models
  • Receptors, Odorant / genetics


  • Apolipoprotein E4
  • Receptors, Odorant