Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study

Patricia L. Kramer, Haiyan Xu, Randall L. Woltjer, Shawn K. Westaway, David Clark, Deniz Erten-Lyons, Jeffrey A. Kaye, Kathleen A. Welsh-Bohmer, Juan C. Troncoso, William R. Markesbery, Ronald C. Petersen, R. Scott Turner, Walter A. Kukull, David A. Bennett, Douglas Galasko, John C. Morris, Jurg Ott

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.

Original languageEnglish (US)
Pages (from-to)2113-2122
Number of pages10
JournalNeurobiology of aging
Issue number12
StatePublished - Dec 2011


  • Alzheimer disease
  • Genome-wide association study
  • Non-demented elderly with AD neuropathology
  • Non-demented elderly without AD neuropathology
  • Reelinneurofibrillary tangles

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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