Association of Blood-Based DNA Methylation Markers With Late-Onset Alzheimer Disease
Blanca Acha, Jon Corroza, Javier Sánchez‐Ruiz de Gordoa, Carolina Cabello, Maitane Robles, Iván Méndez-López, Mónica Macías, Sara Zueco, Miren Roldán, Amaya Urdánoz‐Casado, Ivonne Jericó, María Elena Erro, Daniel Alcolea, Alberto Lleó, Idoia Blanco‐Luquin, Maite Mendióroz, for the iBEAS Study Group
Abstract
<h3>Background and Objective:</h3> There is an urgent need to identify novel non-invasive biomarkers for Alzheimer9s disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of the study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a non-invasive tool to identify late-onset Alzheimer patients, compared to age-matched controls. <h3>Methods:</h3> A case-control study was performed. Blood DNA methylation levels at 46 CpG sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with “probable AD dementia" following NIA-AA guidelines (2011) and age- and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate AD patients from controls. Furthermore, we carried out a stratified analysis by sex. <h3>Results:</h3> Final study cohort consisted of 80 AD patients (age-median (IQR) = 79 (11); 58.8% female) and 100 cognitively healthy controls (age 77 (10); 58% female). A panel including DNA methylation levels at <i>NXN, TREML2</i>, <i>ABCA7</i> and <i>HOXA3</i> genes and plasma pTau181 significantly improved (AUC [95% CI]=0.93[0.89-0.97]) the diagnostic performance of a single pTau181-based model, adjusted for age, sex and <i>APOE</i> ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, <i>HOXA3</i> DNA methylation levels showed consistently associated to AD. <h3>Discussion:</h3> These results highlight the potential translational value of blood-based DNA methylation biomarkers for non-invasive diagnosis of AD. <h3>Registration number and name of registry:</h3> Research Ethics Committee of the University Hospital of Navarre (PI17/02218).