ASSOCIATIONS BETWEEN 263 BLOOD-BASED EPIGENETIC BIOMARKERS AND GLOBAL MYELIN-RELATED MICROSTRUCTURE IN TWO ADULT COHORTS

Myelin, the axonal sheath, ensures efficient neurotransmission and supports cognitive function. Minimally-invasive myelin biomarkers could therefore provide insights into brain health. While circulating proteins may fluctuate, EpiScores (epigenome-wide DNA methylation-based protein proxies) are emerging as stable peripheral biomarkers. Here, we tested whether associations between newly developed EpiScores and myelin-related diffusion MRI (dMRI) metrics are consistent across two independent cohorts with distinct age demographics: STratifying Resilience and Depression Longitudinally (STRADL; 26–82 years) and Lothian Birth Cohort 1936 (LBC1936; 71–74 years). Using penalised regression, we trained (N=15,500) and tested (N=1,000) EpiScores for 325 serum mass-spectrometry-measured proteins, identifying 263 scores that were correlated with respective protein levels (Pearson r>0.1, p<0.05). Principal component analysis of white matter tracts generated latent general fractional anisotropy (gFA), mean (gMD) and radial (gRD) diffusivity, explaining 45–59% of tract variance. Of the 263 EpiScores projected into the cohorts, 95 (STRADL) and 69 (LBC1936) revealed 205 (|β|=0.055–0.14) and 99 (|β|=0.091–0.15) nominally significant EpiScore–dMRI associations (p<0.05). Several dMRI-associated EpiScores corresponded to proteins implicated in myelination, including attractin, fibronectin, and phospholipid transfer protein. Across metrics, 9–18% of EpiScore–dMRI associations overlapped between cohorts, yielding 35 shared and directionally consistent associations. Notably, effect sizes across all EpiScores were correlated between the two cohorts (r_gFA=0.62; r_gMD=0.29; r_gRD=0.47). Overall, we show that multiple blood-based EpiScores capture global myelin-related microstructure, highlighting their potential for indexing brain health. Shared and cohort-specific associations suggest that age-tailored EpiScore panels may appropriately reflect myelin and white matter microstructure at different adult ages.