Proteomic biomarkers of cognitive function, APOE ε4 status, and dementia in Generation Scotland

Untargeted mass spectrometry remains underutilised for blood-based biomarker discovery in dementia research from large cohorts, where affinity-based approaches dominate. To address this, we examined mass-spectrometry-derived proteomic correlates of cognitive function, genetic predisposition to cognitive health, APOE {varepsilon}4 status, and incident dementia. Using multivariate Bayesian regression, we assessed associations between 439 independent mass spectrometry signals and five cognitive outcomes--four cognitive tests and a cognitive function polygenic score--in Generation Scotland (n = 14,258). We observed associations between three cognitive tests (digit symbol, vocabulary and verbal fluency) and a mass spectrometry signal that mapped to selenoprotein P (absolute {beta}range = 0.02 - 0.03, posterior inclusion probability [&ge;] 0.95). Carrying one or two copies of the APOE {varepsilon}4 allele was associated with a lower mass spectrometry signal that mapped to afamin ({beta} = -0.08 and -0.2, respectively, p < 3.1 x 10-4, n = 14,745). A higher mass spectrometry signal that maps to both complement c2 and complement factor B proteins was associated with lower hazard for incident dementia (hazard ratio = 0.75, p < 3.1 x 10-4, ncases = 212 and ncontrols = 6,765) diagnosed up to 17 years after blood sampling. We identified specific independent mass spectrometry signals which may be candidate biomarkers of cognitive function, APOE {varepsilon}4 status, and could aid in the early detection of dementia; however, further replication studies in other populations are required.