Epigenetic scores of blood-based proteins as biomarkers of general cognitive function and brain health

Background Blood-based biomarkers of brain health could provide a cost-effective contribution to detecting individuals at risk of dementia. Epigenetic scores (EpiScores) for blood protein levels have previously associated with several disease outcomes and measures of brain health, however this has typically been limited to single EpiScore analyse. Results Using 84 protein EpiScores as candidate biomarkers, associations with general cognitive function (both cross-sectionally and longitudinally) were tested in three independent cohorts: Generation Scotland (GS), and the Lothian Birth Cohorts of 1921 and 1936 (LBC1921 and LBC1936, respectively). A meta-analysis of general cognitive functioning results in all three cohorts identified 18 EpiScore associations (absolute meta-analytic standardised estimates ranged from 0.03 to 0.14, median of 0.04, FDR P<0.05). Several associations were also observed between EpiScores and global brain volumetric measures in the LBC1936. An EpiScore for the S100A9 protein (a known Alzheimer disease biomarker) was associated with general cognitive functioning (meta-analytic standardised beta: -0.06, P = 1.3 x 10 -9 ), and with time-to-dementia in GS (Hazard ratio: 1.24, 95% confidence interval 1.08 – 1.44, P = 0.003), but not in LBC1936 (Hazard ratio: 1.11, P = 0.32). Conclusions EpiScores might make a contribution to the risk profile of poor general cognitive function and global brain health, and risk of dementia, however these scores require replication in further studies.