Cerebrospinal Aβ11-x and 17-x levels as indicators of mild cognitive impairment and patients' stratification in Alzheimer's disease

In the present work, the concentrations of Ap11-x and A beta 17-x peptides (x = 40 or 42), which result from the combined cleavages of beta-amyloid precursor protein (A beta PP) by beta'/alpha or alpha/gamma-secretases, respectively, were assessed in cerebrospinal fluid (CSF) samples from patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). Specific multiplexed assays were set up using new anti-40 and anti-42 monoclonal antibodies (mAbs) for the capture of these N-truncated A beta peptides and anti-11 or anti-17 mAbs for their detection. The specificity, sensitivity and reproducibility of such assays were assessed using synthetic peptides and human cell models. A beta 11-x and A beta 17-x were then measured in CSF samples from patients with AD (n = 23), MCI (n 23) and controls with normal cognition (n 21). Ap11-x levels were significantly lower in patients with MCI than in controls. Compared with the combined quantification of A beta-42, total Tau (T-Tau) and phosphorylated Tau (P-Tau; AlzBio3, Innogenetics), the association of A beta 11-40, A beta 17-40 and T-Tau improved the discrimination between MCI and controls. Furthermore, when patients with MCI were classified into two subgroups (MCI <= 1.5 or >= 2 based on their CDR-SB (Cognitive Dementia Rating-Sum of Boxes) score), the CSF A beta 17-40/A beta 11-40 ratio was significantly higher in patients with CDR-SB <= 1.5 than in controls, whereas neither A beta 1-42, T-Tau nor P-Tau allowed the detection of this subpopulation. These results need to be confirmed in a larger clinical prospective cohort.