Exploring the epigenetics of Alzheimer disease.

Genome-wide association studies have been tremendously successful at unraveling the genetic architecture of neurological disorders (seehttp://www.genome.gov/gwastudies/ for an updated list). Alzheimer disease is a particularly good example of the power of this technology, with multiple loci already identified.1 Although thepublicationof a susceptibility locus is an important milestone in any disease, it represents only the opening act because the identity of the responsible gene within a locus is not always obvious. Without this knowledge, it becomes difficult (if not impossible) to establish a functional connection between genetic variation and the underlying pathobiology. Not surprisingly, this circumstance is a major challenge now faced by the entire genomics field. Tobridge this gap, amultipronged approachhas beenadopted todelineate theeffect of genetic variationon the expression of neighboring genes (known as expression quantitative trait loci mapping2) and to quantify the effects of epigeneticphenomena in regulatinggene transcription.The term epigenetics covers a gamut ofmechanisms such asDNAmethylation, chromatin remodeling, geneexpression regulationby microRNA, histone modification, and others. The article by Yu and colleagues3 in this issue of JAMA Neurology focuses on the contribution of DNAmethylation in Alzheimer disease loci to the susceptibility for this condition. In its simplest terms,methylation controls geneexpressionby blocking the binding of transcription factors to gene regulatory elements. The higher the methylation in and around a gene, the lower is its expression. In reality, the spatial and temporal biological consequences of methylation are more nuanced, but this paradigm remains useful when interpreting methylationdata.Methylation studies are challenging to performbecause this epigeneticparametervaries across andeven within tissues. For example, the methylation pattern observed inblood cells of an individual significantlydiffers from that in his or her brain.4 A major strength of the study by Yu et al is that they analyzed themethylation status in the tissue involved in the disease process, namely, the brains of several hundred patients diagnosed as having Alzheimer disease. These sampleswere collected aspart of 2 largeprospective cohorts, highlighting the value of such tissue collections, something that needs to be done in other neurological diseases as well. So what did they find? First and foremost, the methylation of 5 loci (SORL1,ABCA7,HLA-DRB5, SLC24A4, and BIN1) was significantly associated with a pathological diagnosis of Alzheimer disease. Within each of these 5 genes, the authors also identified methylation patterns associated with the key pathological changes of Alzheimer disease, namely, β-amyloid load and tau tangle density. Finally, they examined expressiondatagenerated for the samesamples todetermine the effect of methylation on gene expression. Although this last analysis indicatedonlyweakcorrelation, it showcases theability of modern genomics to leverage different data sets. Future analysis of larger cohortsmayhavegreater power to identify such methylation quantitative trait loci.2 In essence, the article byYuandcolleaguesprovides compelling evidence implicating DNA methylation in the pathogenesis of this common form of neurodegeneration. It replicates previous studies5,6 showing that the methylation of ABCA7, BIN1, and SORL1 is important in Alzheimer disease pathogenesis and nominates 2 additional loci as important, namely,HLA-DRB5 and SLC24A4. Plausible biological stories arealreadyemerging for someof thesegenes.Forexample, the protein encoded by the SORL1 gene controls β-amyloid production.7 Reduced SORL1 protein levels (such asmight be expectedwith increasing levels of DNAmethylation in the locus)would lead to a corresponding increase in β-amyloidproduction and an increased risk of dementia. Presumably, data provided in the study by Yu et al will contribute to a deeper understanding of the biology underpinning other loci. Like all good science, the article by Yu and colleagues has limitations and raises compellingquestions. First, is themethylation pattern observed in these postmortem samples present at the start of the neurodegenerative process several decades before autopsy, or did these changes accumulate over the course of the illness as the patient aged?8 Second, DNA methylation in these 5 loci influences the neuropathological substrates ofAlzheimer disease, but does that translate in the clinical setting tomore severe cognitive impairment or amore rapidlyprogressive course?Third, studyingmethylation inautopsymaterial means that one is examining the status of surviving cells that did not degenerate. Is themethylation status inthesesurvivingcells trulyrepresentativeof thecells thathave already died? Fourth, the study by Yu and colleagues focused on the methylation of CpG islands, but it is increasingly recognized thatmethylation occurs outside of these islands and may be important in determining gene expression.9 The answers to such questions are complicated, and somemayhave towait until technology evolves further to allow themethylation status across the genome to be measured in the brain in living patients. DNA methylation, and epigenetics more broadly, represents complex phenomena that likely have central roles in our susceptibility to neurodegeneration. The studybyYuet al representsan importantmilestone inourefforts tounderstand the part of methylation in the pathogenesis of Alzheimer disease. Related article page 15 Opinion