Abstract
Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five gene modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 541 subjects from two cohort studies of brain aging. Two of these transcriptional programs – modules 113 and 114 – relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. These modules are also detectable in the human brain's epigenome, where we replicate these associations. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that VASP, a representative module 5 gene, encodes a protein that is upregulated in activated microglia in AD.
