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P4‐127: Studies of pathologic and immunologic traits integrate the effect of CR1 and CD33 variants on cognitive decline
Author(s) -
Bradshaw Elizabeth,
Chibnik Lori,
Keenan Brendan,
Shulman Joshua,
Schneider Julie,
Bennett David,
De Jager Philip
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1830
Subject(s) - cd33 , microglia , allele , locus (genetics) , immunology , cognitive decline , biology , medicine , disease , gene , genetics , inflammation , dementia , stem cell , cd34
AD-related neuritic amyloid plaque burden (P<10^-7). In a secondary analysis, all 163 CpG also demonstrate strong evidence of association with a pathological diagnosis of AD, and 95% of the dinucleiotides are hypermethylated in AD subjects. Further, when the analysis is limited to 230 subjects with normal cognition at the time of death, association with neuritic plaque burden persists, suggesting that changes in methylation are an early feature of AD. We validate these results using an independent collection of AD and control brains: 58.5% of the genes near these 163 CpGs demonstrate altered transcription levels in AD brains. Finally, using a novel chromatin state map of the frontal cortex, we see that the 163 CpGs are distributed in a number of different chromatin states but appear to be enriched in gene bodies, particularly those that are not transcriptionally active. Conclusions: Robust changes in DNAmethylation are found in the brains of subjects who display evidence of AD-associated neuritic plaque pathology. Most sites are hypermethylated in AD subjects, suggesting a coordinated AD-associated chromatin remodeling in aging brains that is present even in individuals with no cognitive impairment.