Multi‐cohort profiling reveals elevated CSF levels of brain‐enriched proteins in Alzheimer’s disease

• Published in: Annals of clinical and translational neurology 2021-07, Vol.8 (7), p.1456-1470
• Main Authors: Bergström, Sofia, Remnestål, Julia, Yousef, Jamil, Olofsson, Jennie, Markaki, Ioanna, Carvalho, Stephanie, Corvol, Jean‐Christophe, Kultima, Kim, Kilander, Lena, Löwenmark, Malin, Ingelsson, Martin, Blennow, Kaj, Zetterberg, Henrik, Nellgård, Bengt, Brosseron, Frederic, Heneka, Michael T., Bosch, Beatriz, Sanchez‐Valle, Raquel, Månberg, Anna, Svenningsson, Per, Nilsson, Peter
• Format: Article
• Language: English
• Subjects: Adult; Age; Aged; Aged, 80 and over; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - diagnosis; Alzheimer's disease; Alzheimers disease; amphiphysin; Amyloid beta-Peptides - cerebrospinal fluid; Antibodies; Aquaporin 4 - cerebrospinal fluid; association; beta-Synuclein - cerebrospinal fluid; Biochemistry, Molecular Biology; biomarkers; Biomarkers - cerebrospinal fluid; Biotechnology; Bioteknologi; Brain - metabolism; cerebrospinal fluid; Cognitive Dysfunction - cerebrospinal fluid; Cognitive Dysfunction - diagnosis; Cohort Studies; Cross-Sectional Studies; Dementia; Demographics; determinant; Female; GAP-43 Protein - cerebrospinal fluid; Genomics; Humans; Life Sciences; Male; Medicin och hälsovetenskap; Middle Aged; mild cognitive impairment; Nerve Tissue Proteins - cerebrospinal fluid; Neurobiology; neurodegeneration; Neurofilament Proteins - cerebrospinal fluid; Neurons and Cognition; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; pathology; Peptide Fragments - cerebrospinal fluid; Phosphoproteins - cerebrospinal fluid; plasma biomarkers; Protein Array Analysis - methods; Proteins; proteomics; serum neurofilament light; suspension bead array; tau Proteins - cerebrospinal fluid
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.51402

Objective Decreased amyloid beta (Aβ) 42 together with increased tau and phospho‐tau in cerebrospinal fluid (CSF) is indicative of Alzheimer’s disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages. Methods We utilized an antibody‐based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification. Results Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP‐regulated phosphoprotein 21 (ARPP21), growth‐associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of Aβ42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations. Interpretation In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.