Primary age-related tauopathy (PART) and Alzheimer's disease (AD) share hippocampal phospho-tau (p-tau) pathology but differ in p-tau extent and amyloid presence. As a result, PART uniquely enables investigation of amyloid-independent p-tau mechanisms during brain aging. We conducted the first epigenome-wide association (EWAS) study of PART, which yielded 13 new and robust p-tau/methylation associations. We then jointly analyzed PART and AD epigenomes to develop 'TauAge', novel epigenetic clocks that predict p-tau severity in region-specific, age-, and 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 based on PART-vs-AD epigenetic differences discriminates neuropathological diagnoses and stratifies indeterminate cases into 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.

The authors have declared no competing interest.

We wish to thank all the individual study volunteers, tissue donors, and caregivers with whom this work would not be possible. This work was supported by funding from the National Institutes of Health (R01AG066152, P30AG072979, R35GM146978, UE5NS065745, T32AG076411, P01AG066597, P01AG084497) and Penn Institute on Aging. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal. Study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, and the Illinois Department of Public Health (ROSMAP). Additional phenotypic data can be requested at www.radc.rush.edu. Brain banking and neuropathology assessments for the MSBB cohort were supported by NIH grants AG02219, AG05138, and MH064673 and the Department of Veterans Affairs VISN3 MIRECC.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The data presented from the multi-institutional PART working group are from post-mortem tissue donated to the respective institution by the individual's next of kin. All material is de-identified. Research with de-identified autopsy material does not meet the federal regulatory definition of human subject research as defined in 45 CFR part 46 has been deemed exempt from review by the Institutional Review Board of Mount Sinai School of Medicine. The data presented from the Religious Orders Study and Memory and Aging Project are available by controlled access, and use in this study was reviewed by the Resource Sharing Committee of the Rush Alzheimer's Disease Center. The data presented from the Mount Sinai Brain Bank cohort are publicly available.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.