INTRODUCTION: Cognitive reserve (CR) reflects variability in cognitive adaptability that modifies the impact of Alzheimer's disease (AD) pathology on cognition. However, blood-based biomarkers of CR have not been established in prodromal AD. We operationalized CR as memory reserve, defined by the attenuation of the cerebrospinal fluid (CSF) phosphorylated tau threonine 181 (pTau181)-memory association and aimed to identify blood DNA methylation (DNAm) loci involved in memory reserve. METHODS: 𝜀4 allele count, and estimated immune cell-type proportions. For each CpG, linear models tested DNAm, pTau181, and DNAm×pTau181 interaction; inflation was corrected using the bacon method. In addition, we also identified differentially methylated regions (DMRs). Moreover, we constructed a methylation reserve score (MRS) from loci identified in this cohort at baseline and tested its associations with longitudinal memory using linear mixed-effects models in 88 participants with follow-up information. RESULTS: ε4, and baseline pTau181. DISCUSSION: Blood DNAm that moderates the pTau181-memory association may reflect epigenetic correlates of memory reserve (i.e., differential susceptibility to tau-related memory impairment), rather than reflecting variations in pTau181 levels. These DNAm patterns can be summarized as a MRS that, in this cohort, was associated with longitudinal memory trajectories in MCI. Further validation in independent cohorts is warranted.
Lukacsovich et al. (Wed,) studied this question.