DNA Methylation at Core N-Methyl-D-Aspartate (NMDA) Receptor Genes Reveals a Glutamatergic Signature of Aging in Post-COVID Whole Blood With Implications for Long-COVID Neuropsychiatric Sequelae.

Background Cognitive symptoms after SARS-CoV-2 infection, often described as "brain fog," remain difficult to measure objectively and are biologically heterogeneous. DNA methylation may provide a stable, blood-accessible layer of information linking post-COVID immune remodeling, biological aging, and neuropsychiatric vulnerability. We re-analyzed GSE247869, a whole-blood Illumina MethylationEPIC dataset from individuals sampled six months after COVID-19 infection, to identify age-associated methylation signals with translational relevance. The present analysis was designed to characterize age-associated methylation within this post-COVID cohort, not to establish a COVID-19-specific signature or biological age acceleration. Methodology This was a cross-sectional analysis of a single post-COVID cohort, with 94 samples included in the age models and no COVID-19-negative comparator included in the analyzed model. Processed beta values were aligned to metadata, converted to M-values, and modeled at each cytosine-phosphate-guanine (CpG) using ordinary least squares with age and sex as predictors. Differentially methylated positions were corrected by Benjamini-Hochberg false discovery rate (FDR). CpGs were mapped to genes using robust annotation and Illumina manifest fallback. Gene-level signals were integrated using a multi-evidence prioritization score that incorporated statistical strength, effect size, multi-CpG support, direction consistency, known epigenetic-clock membership, and curated pathway membership. Results Within this cohort, the analysis identified 3,467 age-associated CpGs at FDR < 0.05, with an overall hypomethylation bias but focal hypermethylation at canonical aging loci. In total, 11 of 12 reference clock CpGs were recovered, including