Alzheimer disease pathology in cognitively healthy elderly: a genome-wide study.
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.
Kramer
Patricia L
PL
Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA. kramer@ohsu.edu
Xu
Haiyan
H
Woltjer
Randall L
RL
Westaway
Shawn K
SK
Clark
David
D
Erten-Lyons
Deniz
D
Kaye
Jeffrey A
JA
Welsh-Bohmer
Kathleen A
KA
Troncoso
Juan C
JC
Markesbery
William R
WR
Petersen
Ronald C
RC
Turner
R Scott
RS
Kukull
Walter A
WA
Bennett
David A
DA
Galasko
Douglas
D
Morris
John C
JC
Ott
Jurg
J
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000235:genetics*; D003071:Cognition / Q000502:physiology*; D015331:Cohort Studies; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006304:Health Status; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D016875:tau Proteins; C000717127:RELN protein, human; D012697:Serine Endopeptidases
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