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 the ultimate goal of revealing clear risk factors that can help in the diagnosis, prevention and treatment 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 analysis 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 found to be of bimodal structure, with a hypomethylated CpG-poor promoter and a fully methylated 3′-CpG-island, that contains the sequences 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.
Highlights
Alzheimer’s disease (AD) is the most prominent form of dementia among the elderly
Overall DNA methylation From the 12 analyzed CpG-rich regions, 9 were mostly unmethylated (,20% methylation), 2 gene promoters were partly methylated (20–50%) and only one hypermethylated (.50% methylation). This result is in agreement with earlier observation of CpG island methylation patterns on chromosome 6, 20 and 22, where the majority of CpG islands (CGIs) were unmethylated and only a small fraction (9.2%) were hypermethylated [12]
Since each cell type in the brain possesses a characteristic profile of DNA methylation specific to its function, we cannot rule out that the observed methylation patterns could be the consequence of a shift in cellular population heterogeneity, associated with loss of specific cell types in the diseased individuals
Summary
Alzheimer’s disease (AD) is the most prominent form of dementia among the elderly. Despite enormous research efforts, the etiology of AD remains obscure and puzzling. Some genes for some early-onset familial forms of Alzheimer’s disease have been identified (,5% of cases), the overwhelming proportion of diagnosed AD cases remains unexplained These circumstances led to a rethinking of the classical molecular approaches, shifting the emphasis from genetic causative factors to epigenetic and environmental effects. In contrast to monogenic diseases, LOAD exhibits numerous non-Mendelian anomalies that suggest an epigenetic component in disease etiology Such anomalies include among others: 1.) Sporadic cases dominate over familial ones; 2.) estimated concordance rates for monozygotic twins are significantly below 100%, a hallmark of complex non-Mendelian diseases; 3.) differential susceptibility and course of illness in males and females [3,4]; 4.) parent-of-origin effects [5]; 5.) late age of onset; 6.) brain chromatin abnormalities, including aberrant histone modifications; 7.) non-Mendelian inheritance pattern; 8.) abnormal levels of folate and homocysteine, indicative of an abnormal methylation homeostasis in the brain of AD patients; 9.) a disturbed control of the epigenetically regulated circadian clock and 10.) monoallelic expression patterns of susceptibility genes [6]. The epigenome is susceptible to deregulation during early embryonal and neonatal development, puberty and especially old age [7], which is the most important known risk factor for AD
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