In this cohort study of 298 individuals with SCD, steeper slopes of plasma phosphorylated tau 217 (pTau 217), glial fibrillary acidic protein (GFAP), and neurofilament light were associated with cognitive decline, whereas pTau217 and GFAP slopes were associated with progression to mild cognitive impairment or dementia. Here, NEFL is linked to Schnyder corneal dystrophy.