Discovery of cerebrospinal fluid biomarkers for different dementias using mass spectrometry-based proteomics

INTRODUCTION Common forms of dementia include Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Disease specific biomarkers are needed for differential disease diagnosis. METHODS We performed cerebrospinal fluid (CSF) mass spectrometry proteomics on three cohorts (n = 110, n = 112, n = 78) including AD, DLB, FTD, mild cognitive impairment (MCI) with or without abnormal cerebrospinal fluid (CSF) amyloid-beta 1-42 (A beta 1-42) levels (MCI A beta+ and MCI A beta-, respectively) and controls. RESULTS We identified and validated 11, 3, and 5 differentially expressed proteins in AD, DLB, and FTD, respectively. Potential disease specific proteins included fructose-bisphosphate aldolase A (ALDOA), L-lactate dehydrogenase A chain (LDHA), malate dehydrogenase, cytoplasmic (MDH1), and phosphoglycerate mutase 1 (PGAM1), which were upregulated in AD and MCI A beta+ across multiple cohorts and did not display altered levels in DLB and FTD. Validated DLB and FTD proteins were altered in similar directions in other dementia types in at least one other cohort. DISCUSSION Proteomics identified potential disease specific biomarkers in AD which were already altered in the prodromal stage.