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Alzheimer's Disease Meta-Analysis Identifies Novel Differentially Methylated Loci

NEW YORK – Through a meta-analysis of epigenome-wide association studies of Alzheimer's disease, an international team of researchers has identified novel differentially methylated loci associated with the spread of neurofibrillary tangles in different brain regions and across the cortex.

In a paper published on Thursday in Nature Communications, the researchers noted that Alzheimer's EWAS have highlighted neuropathology-associated DNA methylation differences, but that they've been limited in sample size and generally studied different regions of the brain. For their meta-analysis, they combined data from six DNA methylation studies, for a total of 1,453 individuals, and identified differential methylation associated with the neurofibrillary tangles known as Braak stage.

They found 236 significant CpGs in the prefrontal cortex, 95 in the temporal gyrus, and 10 in the entorhinal cortex, with none in the cerebellum. Overall, the researchers said, the cross-cortex meta-analysis identified 220 CpGs that were associated with neuropathology, annotated to 121 genes. Of these, 84 genes have not been previously reported at this significance threshold.

"Our study is the largest of its kind, giving important insights into genomic areas that could one day provide the key to new treatments," Katie Lunnon, a professor at the University of Exeter and the study's senior author, said in a statement. "The next step for this work is to explore whether these epigenetic changes lead to measurable changes in the levels of genes and proteins being expressed. This will then allow us to explore whether we could repurpose existing drugs that are known to alter the expression levels of these genes and proteins, to effectively treat dementia."

The prefrontal cortex represented the researchers' largest dataset with 961 samples, and they identified 236 significant differentially methylated positions, 193 of which were annotated to 137 genes, with 43 unannotated loci. Previous EWAS of the prefrontal cortex had consistently reported the HOXA gene cluster as a region that is hypermethylated in Alzheimer's, with a cell-type specific EWAS demonstrating this to be derived from the neurons. Indeed, the researchers reported that the most significant differentially methylated position they found in the prefrontal cortex resided in HOXA3, with a further 16 significant differentially methylated positions also annotated to this gene.

"This locus appeared to be particularly hypermethylated with higher Braak stage in the prefrontal cortex, and to a slightly lesser extent in the temporal gyrus," the authors wrote.

They also identified a number of novel genes, including some with multiple significant differentially methylated positions. One noteworthy novel position in the prefrontal cortex was annotated to ADAM10, a gene that encodes α-secretase, which cleaves APP in the non-amyloidogenic pathway.

They conducted a similar meta-analysis of their temporal gyrus EWAS datasets, which identified 95 significant probes, 75 of which were annotated to 53 genes. A meta-analysis of entorhinal cortex datasets identified 10 significant probes, annotated to eight genes, including the ANK1 and SLC15A4 genes.

Taken together, along with a lack of significant probes in the cerebellum, the data suggested that DNA methylation changes in Alzheimer's are cortex cell type specific, the researchers said. This observation correlates with the absence of neurofibrillary tangles in the cerebellum, although some diffuse amyloid-beta plaques have been reported in that region.

The researchers then combined data across the different cortical tissues to identify common differentially methylated loci. They found 220 significant probes, 168 of which were annotated to 121 genes, and observed similar DNA methylation patterns across all cortical cohorts and tissues for the 220 probes. In total, 154 of the differentially methylated positions were hypermethylated, and 66 were hypomethylated.

The most significant probe in the cross-cortex analysis was cg12307200, which was located in an intergenic region between the TPRG1 and LPP genes. This probe had previously been reported as having a significant association with neuritic plaque burden and postmortem diagnosis.

The researchers also reported that the cross-cortex meta-analysis identified 174 novel significant differentially methylated positions, annotated to 102 genes. Although 11 of these genes had previously been reported, the remaining 96 represent robust novel loci in Alzheimer's, and many of these novel genes had multiple significant probes.

"A number of these loci are novel and warrant further study to explore their role in disease etiology," the authors concluded. "We highlight that the nominated epigenetic changes are largely independent of genetic effects."