Abstract
Abstract Background Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease and that DNAm differences can be detected in the blood of AD subjects. Because access to human brain tissues is primarily limited to postmortem samples, most studies have correlated blood DNAm with clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Thus, the association of blood DNAm with changes in AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. Method CSF biomarkers are well‐established AD endophenotypes and correlate significantly with neuropathology scores measured on postmortem brain samples. In this study, we performed a comprehensive analysis to identify blood DNA methylation associated with CSF pathological biomarkers for AD in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Our study included matched samples of whole blood DNA methylation, CSF Aβ 42 , phosphorylated tau 181 (pTau 181 ), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 cognitively normal, 79 AD cases). Result We identified a number of novel associations between blood DNAm and CSF Aβ 42 , pTau 181 , and total tau biomarkers, demonstrating that changes in various pathological processes in the CSF are also reflected in the blood epigenome. Overall, the CSF biomarker‐associated DNAm is relatively distinct in cognitively normal (CN) and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our pathway analysis of CSF biomarker associated‐DNAm from CN subjects revealed that biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood. Conclusion Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.