CSF proteomic signature predicts progression to Alzheimer's disease dementia

INTRODUCTION: Individuals in the Alzheimer's disease (AD) continuum with mild cognitive impairment (prodromal AD) are at increased risk to develop dementia. Still, underlying pathophysiological processes remain unclear. We studied whether cerebrospinal fluid (CSF) proteome changes are related to time to clinical progression in prodromal AD. METHODS: We measured 671 CSF proteins in 49 prodromal AD individuals (67±7 years old, 22 [45%] female) from the Amsterdam Dementia Cohort. Associations of protein levels with time to dementia onset were tested with Cox regression models, followed by biological pathway enrichment analysis. RESULTS: Eighteen (36%) individuals developed dementia during follow‐up. In total, 128 (98%) proteins were associated with a 1.4‐ to 17‐fold increased risk of progression to dementia (all P < .05). These proteins showed enrichment for immune system processes, signal transduction, neuronal death, and neurodevelopmental biology. DISCUSSION: CSF proteome changes related to rate of progression to dementia can be detected in prodromal AD, providing more insight into processes involved in early AD pathophysiology.