Age-specific epigenetic drift in late-onset Alzheimer's disease

Sun Chong Wang, Beatrice Oeize, Axel Schumacher

Research output: Contribution to journalArticlepeer-review

401 Scopus citations

Abstract

Despite an enormous research effort, most cases of late-onset Alzheimer's disease (LOAD) still remain unexplained and the current biomedical science is still a long way from ultimate goal of revealing clear risk factors that can help in the diagnosis, prevention and treatement of the disease. Current theories about the development of LOAD hinge on the premise that Alzheimer's arises mainly from heritable causes. Yet, the complex, non-Mendelian disease etiology suggests that an epigenetic component could be involved. Using MALDI-TOF mass spectrometry in post-mortem brain samples and lymphocytes, we have performed an anaylsis of DNA methylation across 12 potential Alzheimer's susceptibility loci. In the LOAD brain samples we identified a notably age-specific epigenetic drift, supporting a potential role of epigenetic effects in the development of the disease. Additionally, we found that some genes that participate in amyloid-β processing (PSEN1, APOE) and methylation homeostasis (MTHFR, DNMT1) show a significant interindividual epigenetic variability, which may contribute to LOAD predisposition. The APOE gene was fond to be of bimodal structure, with a hypomethylated CpG-poor promoter and fully methylated 3′-CpG-island, that contains the sequence for the ε4-haplotype, which is the only undisputed genetic risk factor for LOAD. Aberrant epigenetic control in this CpG-island may contribute to LOAD pathology. We propose that epigenetic drift is likely to be a substantial mechanism predisposing individuals to LOAD and contributing to the course of disease. Copyright:

Original languageEnglish
Article numbere2698
JournalPLoS ONE
Volume3
Issue number7
DOIs
StatePublished - 16 Jul 2008

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