NOVEL CSF PROTEIN BIOMARKERS FOR SPECIFIC AND DIFFERENTIAL DIAGNOSIS OF AD

Differential diagnosis of the most common forms of dementias (Alzheimer's disease -AD-, Lewy body dementia -LBD- and Frontotemporal dementia –FTD-) remains challenging, hampering the development of successful therapies. We aimed to identify novel CSF protein signatures discriminating AD, DLB and FTD by mapping the cerebrospinal fluid (CSF) proteome from a large well-defined dementia cohort using a novel and sensitive proteomic array that can be smoothly translated into a diagnostic assay. CSF samples from patients with AD (n=123), DLB (n=74), FTD (n=116) and non-demented controls (SCD, n=173) were analyzed using an innovative technology validated for CSF analysis and able to measure the concentration of 981 proteins (Olink antibody-based array). Differences in the protein expression profile were analyzed by GlobalTesting. We identified novel CSF protein signatures that successfully discriminate AD from DLB (p=0.042, 9 proteins), FTD (p=0.007, 31 proteins) and SCD (p=0.0004, 61 proteins); which included also proteins known to be differentially regulated between groups (e.g. calsyntenin, contactins, matrix-metalloproteinases). The novel proteins identified covered different mechanisms related to AD pathogenesis (autophagy, inflammation, cytoskeleton remodeling, calcium-dependent signaling). We unraveled novel CSF protein signatures able to discriminate AD patients from patients with other dementias (FTD and DLB) and non-demented controls. Further validation may provide a new tool for specific and differential diagnosis of AD, facilitating the development of successful therapies. Many of the protein changes identified have not been associated previously with AD, FTD or DLB, providing also new insights into the pathophysiology of the different dementias.