Proteomic biomarkers of cognitive function, <i>APOE</i> 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, <i>APOE</i> 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 <i>APOE</i> 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, <i>APOE</i> ε4 status, and could aid in the early detection of dementia; however, further replication studies in other populations are required.