DNA methylation profiling of neuron and glia for the dissection of cell type, age and Alzheimer’s disease-specific changes in the human brain

Alzheimer’s disease (AD) is a progressive brain disorder caused by altered neuronal and glial cell functions. Illumina 450K profiling of cells (nuclei) sorted from post- mortem human brains allowed us assigning cell type- specific epigenetic changes to aging and AD progression. Among a few thousand cell type-specific differentially methylated CpGs (DMCGs) changing with age we identify prominent clusters in the AD genes, CLU, SYNJ2, ANK1 and MCF2L. A distinct set of age independent AD-specific DMCGs shows strong cell specific changes in the genes TOLLIP, BACE2, PKAR1B, PDE9A, ROBO2, FERMT2, UGT8, SPON1, INPP5D, LNFG and SRPK2. Some AD-specific DMCGs even reveal incremental changes with advancing BRAAK stages. In summary we observe a striking presence of DMCGs in major LOAD genes establishing novel connections between genetic and epigenetic contributions to AD. In addition the cell-specific association allows to functionally discriminate epigenetic effects of aging from those related to AD in the human brain. Bulk and cell sorted post-mortem frontal cortex samples