CSF proteome profiling reveals a protein panel detecting amyloidosis and progression to dementia in cognitively unimpaired individuals

Abstract

AbstractBackgroundUnderstanding the earliest biochemical changes related to Alzheimer´s disease (AD) pathology is essential for the development of biomarkers and disease‐modifying therapies. Here, we aimed to map the cerebrospinal fluid (CSF) proteomic changes associated with amyloid ß (Aß) pathology in cognitively unimpaired individuals and identify a panel of CSF biomarkers detecting amyloid positivity as well as clinical progression to dementia.MethodProximity extension‐based multiplex immunoassays were used to measure 614 proteins in 297 CSF samples from cognitively unimpaired controls with and without amyloid pathology (232 CON/Aβ‐ (age: 68±8; sex: 37% female) and 65 CON/Aβ+ (age: 65±7; sex: 49% female) from the Amsterdam Dementia cohort. A total of 39 cases (13%) progressed to mild cognitive impairment (MCI; n = 19) or dementia (n = 20). An additional cognitively unimpaired control cohort from the EMIF‐twin60+ study (103 CON/Aβ‐ and 19 CON/Aβ+) was used to validate the panel. Data was analysed using nested linear models adjusted for multiple testing and penalized generalized linear modelling.ResultWe identified 110 CSF proteins with different levels in CON/Aβ+ compared to Aβ‐ (q<0.05). Proteins were enriched in processes related to proteolysis, enzyme activation and immunity. Classification modelling revealed a panel of 12‐CSF markers that detect amyloid positivity with high accuracy in both the discovery (AUC: 0.93) and validation (AUC: 0.89) cohorts. This panel also predicted clinical progression to MCI and dementia with high accuracy (AUC: 0.83). Chow´s test analysis revealed a structural change in the relation between a subset of these proteins and CSF Aβ42 before the amyloid positivity threshold.ConclusionOverall, this study provides novel pathophysiological leads associated to distinct biological processes in individuals at risk of developing AD‐dementia and provides potential biomarker tools for clinical settings or trials.