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 (Aβ1–42) levels (MCI Aβ+ and MCI Aβ-, 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 Aβ+ 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. Highlights: We studied cerebrospinal fluid (CSF) proteomic alterations in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Proteins with altered CSF levels were associated with immune related processes in AD, DLB, and FTD, glycolytic processes in AD and amyloid-beta positive mild cognitive impairment (MCI Aβ+), and synaptic processes in FTD. MCI Aβ+ and MCI Aβ- displayed divergent proteomic changes, with MCI Aβ+ being more similar to AD, while alterations in MCI Aβ- were difficult to relate to any of the dementias studied. Glycolytic protein levels were specifically upregulated in AD and MCI Aβ+ in our cohorts and in previously published cohorts, while these were unaltered in DLB and FTD.