Received on March 21, 2005
Accepted on June 15, 2005

Proteomics and Protein Markers

Amino-Truncated -Amyloid₄₂ Peptides in Cerebrospinal Fluid and Prediction of Progression of Mild Cognitive Impairment

¹ Innogenetics NV, Gent, Belgium
² Neurotec, Department of Geriatric Medicine, Huddinge University Hospital, Stockholm, Sweden
³ Department of Clinical Neuroscience, Department of Psychiatry, Göteborg University, Mölndal, Sweden
⁴ Department of Clinical Neuroscience, Experimental Neuroscience, Sahlgrenska University Hospital, Mölndal, Sweden

^* To whom correspondence should be addressed. E-mail: hugovdr{at}innogenetics.be.

Background: Early identification of patients with mild cognitive impairment (MCI) progressing to Alzheimer disease (MCI-AD) by use of biomarkers in cerebrospinal fluid (CSF) is an essential step toward improving clinical diagnosis and drug development. We evaluated whether different -amyloid₄₂ (A₄₂) peptides can add further information to the combined use of tau and A_1-42 for predicting risk of progression of MCI to AD.

Methods: We used xMAP^® technology to simultaneously quantify different A₄₂ peptides modified at the amino terminus, tau, and phosphorylated tau (P-tau_181P) in CSF. A₄₂ peptide concentrations were measured by use of immunoreactivity toward A monoclonal antibodies [3D6 (A_42-3D6), WO2 (A_42-WO2), 6E10 (A_42-6E10), and 4G8 (]A_42-4G8)]. The discriminant ability of the markers was evaluated by ROC curve analysis.

Results: The areas under the curves for the separation of MCI-AD from nonprogressing MCI (MCI-N) was significantly higher when we used A_42-3D6/A_42-WO2, A_42-3D6/A_42-6E10, or A_42-3D6/A_42-4G8 compared with A_42-3D6. In addition, differentiation of MCI-N from MCI-AD was improved by quantification of full-length A_1-42 (A_42-3D6) compared with A_42-WO2, A_42-6E10, or A_42-4G8. Several A₄₂ peptides truncated at the amino terminus (A_11-42 and A_8-42) were identified in CSF by surface-enhanced laser desorption/ionization time-of-flight technology.

Conclusion: The CSF markers tau, A₄₂ forms, and P-tau_181P, when used as adjuncts to clinical diagnosis, have the potential to help identify AD pathology and could be a valuable asset for early AD diagnosis.