Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease

Raffaella Nativio, Greg Donahue, Amit Berson, Yemin Lan, Alexandre Amlie-Wolf, Ferit Tuzer, Jon B. Toledo, Sager J. Gosai, Brian D. Gregory, Claudio Torres, John Q. Trojanowski, Li San Wang, F. Brad Johnson, Nancy M. Bonini, Shelley L. Berger

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

Abstract

Aging is the strongest risk factor for Alzheimer's disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We found that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes with distinctive functional roles. Furthermore, we discovered an association between the genomic locations of significant H4K16ac changes with genetic variants identified in prior AD genome-wide association studies and with expression quantitative trait loci. Our results establish the basis for an epigenetic link between aging and AD.

Original languageEnglish (US)
Pages (from-to)497-505
Number of pages9
JournalNature Neuroscience
Volume21
Issue number4
DOIs
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Neuroscience(all)

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