Relationship Between β-Secretase, Inflammation and Core Cerebrospinal Fluid Biomarkers for Alzheimer's Disease

Background: Biomarkers in the cerebrospinal fluid (CSF) can track specific pathophysiological pathways underlying Alzheimer's disease (AD). The connection between these biomarkers remains unclear. Objective: To study six CSF biomarkers in a clinical cohort of patients with different neurodegenerative conditions. Methods: We measured markers of amyloid-beta protein precursor (A beta PP) processing (A beta(42), sA beta PP beta, beta-secretase activity), neuronal damage (total tau, p-tau), and inflammation (YKL-40) in CSF from 194 participants with the following diagnoses: subjective cognitive impairment or non-amnestic mild cognitive impairment (na-SCI, n = 44), amnestic mild cognitive impairment (aMCI, n = 45), dementia of the Alzheimer type (DAT, n = 59), frontotemporal dementia (FTD, n = 22), and 24 cognitively normal controls. We compared biomarkers between clinical groups and CSF-profile groups, and we analyzed the correlation between biomarkers. Results: CSF levels of sA beta PP beta were decreased in FTD patients compared to the other groups. YKL-40 was elevated in DAT and FTD, and also in aMCI patients. CSF A beta(42) correlated positively with beta-secretase activity (R-S = 0.262) and sA beta PP beta (R-S = 0.341). CSF YKL-40 correlated positively with total tau (R-S = 0.467) and p-tau (R-S = 0.429). CSF p-tau and sA beta PP beta contributed significantly to distinguish DAT from FTD. Conclusions: CSF biomarkers of A beta PP processing correlate with each other and are decreased in FTD. The inflammatory marker YKL-40 is increased in different neurodegenerative diseases, even in early stages, and it correlates with biomarkers of neurodegeneration. This suggests that inflammation is a common feature in AD and FTD. A combination of CSF biomarkers tracking distinct pathophysiological processes may be useful to classify subjects with neurodegenerative conditions.