Epigenome‐Wide‐Association‐Scan Reveals Epigenetic Profile Changes Using Neurofilament Light as a Neurodegeneration Proxy Biomarker in Mexican Americans

Abstract

AbstractBackgroundRecent literature shows Alzheimer’s Disease (AD) has both genetic and epigenetic components resulting in disease manifestation. Furthering our prior work on AD epigenetics in the Health and Aging Brain Study – Health Disparities (HABS‐HD) participants, we seek to identify differential CpG methylation profiles of Neurofilament Light (NfL) as a proxy for neurodegeneration in Mexican‐American participants with Normal Cognition (NC) or Mild Cognitive Impairment (MCI).MethodUsing data from the Epigenome Wide Association Scan (EWAS) that our group already published for 90 Mexican Americans in HABS‐HD (formerly Healthy Aging in Latino Elders Study [HABLE]), we conducted preliminary analysis in 32 individuals (NC = 21, MCI = 11) to assess the role of epigenetic markers in neurodegeneration among Mexican Americans. We performed the EWAS using the AT(N) biomarker, Neurofilament Light (NfL), as the outcome in our pilot group of 32 Mexican Americans. We first tested if the NfL data was normalized using the Shapiro Test, then tested NfL differences between NC and MCI with a Wilcox Test. We further tested CpG sites with NfL using a disease‐stratified and unstratified model with linear regression modelling and adjusted for covariates, such as age, gender, and education.ResultResults of our analysis for the association between CpG methylation profiles and NfL showed 14 down‐regulated CpG sites and 1 up‐regulated CpG site with significant P values after multiple testing. These significant CpG sites residing in LRP4 (Chr11p11.2), ABCB9 (Chr12q24.31), and KIAA (Chr13q14.13) are implicated in the CpG methylation profile changes. These genes have been implicated in AD pathogenesis by other molecular studies. When we stratified NfL count by disease subtype, we did not find any significance in this dataset. We are expanding our ongoing work to identify methylation profiles of NfL in a larger cohort.ConclusionOur pilot findings are critical in understanding epigenetic profiles of biomarkers for neurodegeneration. Results suggest that epigenetics play a major role in the pathophysiology of AD development and manifestation, and that this effect may be different by ethnicity. Future studies will include a larger sample size, longitudinal analyses, and additional ethnic groups to help bridge the health disparities gap in the literature.