INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are reliable predictors of future AD risk. We investigated whether pre-clinical changes in AD CSF biomarkers are reflected in blood DNA methylation (DNAm) levels in cognitively normal participants. METHODS: We profiled blood-based DNAm with the EPIC array in participants without a diagnosis of cognitive impairment in the Emory Healthy Brain Study (EHBS
N=495) and ADNI (N=122). Their CSF Aβ42, tTau, and pTau levels were quantified using Elecsys immunoassays. We conducted epigenome-wide association studies to assess associations between DNAm and CSF biomarkers of AD. RESULTS: In EHBS, no loci were Bonferroni-significant after adjusting for confounding factors. In ADNI, two loci were significant, but they were not replicated in EHBS. There was little agreement between the top loci from EHBS and ADNI. DISCUSSION: Our study showed little evidence of an association between differential blood-based DNAm and pre-clinical AD CSF biomarkers.