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Thus, PART provides a human model to understand the mechanisms of age and amyloid-independent modifiers of p-tau. Given the dynamics of DNA methylation over the lifespan, we (1) performed an epigenome-wide association study of PART that nominated 13 loci associated with p-tau; (2) developed two novel epigenetic clocks predictive of p-tau in age-, and \u00df-amyloid-independent manners: \u201cTauSeverity\u201d relates hippocampal p-tau severity in PART and AD and synaptic transmission genes; \u201cTauSpread\u201d relates to p-tau spread to frontal cortex of AD and neuroinflammatory genes; and (3) a machine learning classifier that identifies low- and high resilience individuals with overlapping neuropathological features but distinct epigenetic, transcriptomic, and clinical features. We conclude that the epigenome contributes to the severity and spread of p-tau pathology, guided by distinct pathways with cognitive consequences.<\/jats:p>","DOI":"10.1101\/2024.11.07.24316933","type":"posted-content","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T13:15:17Z","timestamp":1731417317000},"source":"Crossref","is-referenced-by-count":2,"title":["Epigenetic signatures of regional tau pathology and cognition in the aging and pathological brain"],"prefix":"10.64898","author":[{"given":"David C.","family":"Goldberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7007-2371","authenticated-orcid":false,"given":"Anil 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