Alzheimer's Precision Neurology: Epigenetics of Cytochrome P450 Genes in Circulating Cell-Free DNA for Disease Prediction and Mechanism.

Precision neurology combines high-throughput technologies and statistical modeling to identify novel disease pathways and predictive biomarkers in Alzheimer's disease (AD). Brain cytochrome P450 (CYP) genes are major regulators of cholesterol, sex hormone, and xenobiotic metabolism, and they could play important roles in neurodegenerative disorders. Increasing evidence suggests that epigenetic factors contribute to AD development. We evaluated cytosine ('CpG')-based DNA methylation changes in AD using circulating cell-free DNA (cfDNA), to which neuronal cells are known to contribute. We investigated CYP-based mechanisms for AD pathogenesis and epigenetic biomarkers for disease detection. We performed a case-control study using 25 patients with AD and 23 cognitively healthy controls using the cfDNA of CYP genes. We performed a logistic regression analysis using the MetaboAnalyst software computer program and a molecular pathway analysis based on epigenetically altered CYP genes using the Cytoscape program. We identified 130 significantly (false discovery rate correction q-value < 0.05) differentially methylated CpG sites within the CYP genes. The top two differentially methylated genes identified were