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

Abstract

Objective: Decreased amyloid beta (Ab) 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 AETI-ONOMY 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 Ab42 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.

Sex differences in plasma p-tau181 associations with Alzheimer’s disease biomarkers, cognitive decline, and clinical progression

“…Conversely, higher levels of tau pathology in the brain can trigger a cascade of neuroinflammatory responses leading to BBB breakdown [37]. Studies suggest that aquaporin 4, a water channel that is critically involved in the glymphatic clearance of CSF solutes, is downregulated in AD, which may lead to reduced tau clearance from the central nervous system [38][39][40]. Future studies should address the extent to which sex differences in tau clearance pathways and tau-mediated BBB breakdown exist and determine whether they impact sex differences in plasma versus CSF p-tau181 concentrations.…”

Aquaporin-4 and Cognitive Disorders

“…On autopsy, higher AQP4 expression was found in the brain tissue of patients with AD and cerebral amyloid angiopathy (CAA) than in that of controls, suggesting that AQP4 may play a role in the damage of water transport in AD and CAA. [ 10 ] Recent multicohort profiling also demonstrated significantly higher AQP4 expression in the CSF of AD patients than in that of normal controls, which suggests it potential as a biomarker to reflect AD progression [ 11 ].…”

A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study

“…In order to fully confirm the target specificity there is a need for further validation and characterisation, utilizing more antibodies in either single binder assays or sandwich assay or other orthogonal methods such as parallel reaction monitoring (PRM) assays or epitope mapping. This is exemplified by the thorough characterisation of NEFM investigated using both sandwich assays [ 9 ] and PRM assay [ 23 ] and AQP4 with a sandwich assay [ 26 ]. All used antibodies from the Human Protein Atlas have been validated and confirmed to only bind its specific target in a protein array format ( www.proteinatlas.org ).…”

“…The samples were distributed in 96-well PCR plates in a constrained randomized fashion, based on diagnostic group (AMC, PMC or NC), sex and age. Target proteins ( n = 174) were selected based on previous internal published and unpublished neuroproteomic efforts [ 9 , 21 – 26 ], complemented with additions from literature. Antibodies towards 169 of the 174 proteins were selected from the Human Protein Atlas project ( www.proteinatlas.org ) and antibodies towards the remaining five proteins were included from other providers.…”