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

TitleAlzheimer disease pathology in cognitively healthy elderly: a genome-wide study.
Publication TypeJournal Article
Year of Publication2011
AuthorsKramer PL, Xu H, Woltjer RL, Westaway SK, Clark D, Erten-Lyons D, Kaye JA, Welsh-Bohmer KA, Troncoso JC, Markesbery WR, Petersen RC, R Turner S, Kukull WA, Bennett DA, Galasko D, Morris JC, Ott J
JournalNeurobiol Aging
Volume32
Issue12
Pagination2113-22
Date Published2011 Dec
ISSN1558-1497
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Cell Adhesion Molecules, Neuronal, Cognition, Cohort Studies, Extracellular Matrix Proteins, Female, Genome-Wide Association Study, Health Status, Humans, Longitudinal Studies, Male, Nerve Tissue Proteins, Neurofibrillary Tangles, Phosphorylation, Polymorphism, Single Nucleotide, Serine Endopeptidases, Signal Transduction, tau Proteins
Abstract

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.

DOI10.1016/j.neurobiolaging.2010.01.010
Alternate JournalNeurobiol. Aging
PubMed ID20452100
PubMed Central IDPMC2990809
Grant ListP50-AG08671 / AG / NIA NIH HHS / United States
R01-AG026916 / AG / NIA NIH HHS / United States
P01-AG03991 / AG / NIA NIH HHS / United States
P30 AG008017-209005 / AG / NIA NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P50-AG005146 / AG / NIA NIH HHS / United States
P30-AG10161 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
R01 AG026916-04 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
P30-AG008017 / AG / NIA NIH HHS / United States
R01-AG17917 / AG / NIA NIH HHS / United States
P50-AG16574 / AG / NIA NIH HHS / United States
P30-AG028377 / AG / NIA NIH HHS / United States
P30 AG008017 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P30-AG10129 / AG / NIA NIH HHS / United States
P30-AG028383 / AG / NIA NIH HHS / United States
P50-AG05681 / AG / NIA NIH HHS / United States
U01-AG016976 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
R01 AG026916 / AG / NIA NIH HHS / United States
U01-AG06786 / AG / NIA NIH HHS / United States
U01 AG006786 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
P50-AG05131 / AG / NIA NIH HHS / United States