Epigenetic signatures of regional tau pathology and cognition in the aging and pathological brain.

Primary age-related tauopathy (PART) and Alzheimer's disease (AD) share hippocampal phospho-tau (p-tau) pathology but differ in p-tau extent and ß-amyloid presence. As a result, PART uniquely enables investigation of amyloid-independent p-tau mechanisms during brain aging. We conducted an epigenome-wide association (EWAS) study of PART, nominating 13 new and robust p-tau/methylation associations. We then jointly analyzed PART and AD epigenomes to develop novel epigenetic clocks, "TauAge", that predict p-tau severity in region-specific, age-, and ß-amyloid-independent manners. Integrative transcriptomic analyses revealed that genes involved in synaptic transmission are related to hippocampal p-tau severity in both PART and AD, while neuroinflammatory genes are related to frontal cortex p-tau severity in AD only. Further, a machine learning classifier trained on PART-vs-AD epigenetic differences stratifies an independent cohort of neuropathologically indeterminate cases into pathological subgroups with disparity in cognitive impairment. Together, these findings demonstrate the brain epigenome's substantial role in linking tau pathology to cognitive outcomes in aging and AD.