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 ε4 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 β_range = 0.02 - 0.03, posterior inclusion probability ≥ 0.95). Carrying one or two copies of the APOE ε4 allele was associated with a lower mass spectrometry signal that mapped to afamin (β = -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, n_cases = 212 and n_controls = 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 ε4 status, and could aid in the early detection of dementia; however, further replication studies in other populations are required.