Cerebrospinal Aß11-x and 17-x levels as indicators of mild cognitive impairment and patients' stratification in Alzheimer's disease.

ABSTRACT

In the present work, the concentrations of Aß11-x and Aß17-x peptides (x=40 or 42), which result from the combined cleavages of ß-amyloid precursor protein (AßPP) by ß'/α or α/γ-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 Aß 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. Aß11-x and Aß17-x were then measured in CSF samples from patients with AD (n=23), MCI (n=23) and controls with normal cognition (n=21). Aß11-x levels were significantly lower in patients with MCI than in controls. Compared with the combined quantification of Aß1-42, total Tau (T-Tau) and phosphorylated Tau (P-Tau; AlzBio3, Innogenetics), the association of Aß11-40, Aß17-40 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 Aß17-40/Aß11-40 ratio was significantly higher in patients with CDR-SB ≤1.5 than in controls, whereas neither Aß1-42, T-Tau nor P-Tau allowed the detection of this subpopulation. These results need to be confirmed in a larger clinical prospective cohort.