Biomarkers Consortium - Use of Targeted Multiplex Proteomic Strategies to Identify CSF-Based Biomarkers in Alzheimer’s Disease

The Problem

Early diagnosis of Alzheimer’s disease can improve clinicians’ ability to track the progression of the disease and to treat patients. However, clinicians lack reliable, cost-effective methods to diagnose patients with early-stage AD.

The Solution

This project evaluated whether cerebrospinal fluid-based tests can diagnose early-stage Alzheimer’s disease and track the disease’s progression, ultimately improving clinicians’ ability to treat patients with AD.

Overview

The AD Targeted Cerebrospinal Fluid (CSF) Proteomics Project, completed in 2015 as the second stage of a multi-phased effort, used samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to qualify multiplex panels in cerebrospinal fluid (CSF), aiming to identify biomarkers for diagnosis of Alzheimer’s disease (AD) and monitoring of their disease progression. This project leveraged ADNI CSF samples that were approved for use in assessing the utility of AD biomarker panels. Data are now publicly available via the University of Southern California’s Laboratory of Neuroimaging (LONI).

Goals

To validate a multiplex immunoassay panel as a tool to diagnose and monitor disease progression in the ADNI cohort, using CSF samples.
To examine Beta-Site APP Cleaving Enzyme (BACE-1) levels and enzymatic activity in CSF from the ADNI cohort as a diagnostic biomarker of AD dementia.
To validate a Multiple Reaction Monitoring (MRM) mass spectrometry panel in the ADNI cohort, using CSF samples.

Partners

Public-Sector Partners

National Institute on Aging (NIA)

Private-Sector Partners

Eisai Inc
Genentech, Inc.
Janssen L.P.
Eli Lilly and Company
Merck Sharp & Dohme Corp.
Pfizer Inc
Takeda Pharmaceuticals International, Inc.

Results & Accomplishments

Data and Publications

Results from the project have been uploaded to the ADNI LONI website and generated two published articles. In particular, this project allowed for the validation of a targeted mass spectrometry-based assay for the qualification of candidate AD biomarkers. Several peptides were identified as potential diagnostic or prognostic (predicting progression from MCI to AD) markers. Further study results demonstrated that there is no diagnostic utility of CSF BACE-1 enzymatic activity and concentration to differentiate among healthy elderly, mild cognitively impaired and AD individuals.

Scientific Publications

Development and evaluation of a multiplexed mass spectrometry based assay for measuring candidate peptide biomarkers in Alzheimer’s Disease Neuroimaging Initiative (ADNI) CSF. Spellman, D. S., Wildsmith, K. R., Honigberg, L. A., Tuefferd, M., Baker, D., Raghavan, N., Nairn, A. C., Croteau, P., Schirm, M., Allard, R., Lamontagne, J., Chelsky, D., Hoffmann, S., Potter, W. Z., Alzheimer’s Disease Neuroimaging Initiative. Prot. Clin. Appl. 2015; 9:715-731
Soluble BACE-1 Activity and sAβPPβ Concentrations in Alzheimer’s Disease and Age-Matched Healthy Control Cerebrospinal Fluid from the Alzheimer’s Disease Neuroimaging Initiative-1 Baseline Cohort. Savage, M. J., Holder, D. J., Wu, G., Kaplow, J., Siuciak, J. A., Potter, W. Z. J. Alz. Dis. 2015; 46(2): 431-440

Biomarkers Consortium – Use of Targeted Multiplex Proteomic Strategies to Identify CSF-Based Biomarkers in Alzheimer’s Disease