CSF proteome profiling across the Alzheimer’s disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels
Selected publication · Nature Aging, 2022
del Campo M., Peeters C., Johnson E., Vermunt L., Hok-A-Hin Y., van Nee M., Chen-Plotkin A., Irwin D., Hu W., Lah J., Seyfried N., Dammer E., Herradon G., Meeter L., van Swieten J., Alcolea D., Lleó A., Levey A., Lemstra A., Pijnenburg Y., Visser P., Tijms B., van der Flier W., Teunissen C.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Neurology | Pathophysiology Patient Stratification | CSF |  Olink Target 96 |
Editor's note
In a striking example of how PEA technology can be used and scaled across the protein biomarker discovery, development and validation process, Charlotte Teunissen’s group from UMC Amsterdam first screened almost 700 CSF proteins in patients with Alzheimer’s Disease (AD) and other forms of dementia, using multiple Olink Target 96 panels. From more than 100 disease-associated proteins identified, data-driven modeling derived an 8-protein that stratified patients with AD and Aβ+ mild cognitive impairment from controls, as well as a 9-protein signature to discriminate AD from non-AD dementia, both with extremely high accuracy. These were well-replicated in a separate validation cohort and resulted in the development of custom PEA panels based on the two signatures that were successfully validated in external, independent cohorts.
The authors commented on the value of using a scalable, single-technology proteomic methodology for their work, stating, “Importantly, the technology used allowed us to efficiently translate these panels into customized assays and validate them in an independent cohort, underpinning the effectiveness of the workflow used for biomarker development”.
Abstract
Development of disease-modifying therapies against Alzheimer’s disease (AD) requires biomarkers reflecting the diverse pathological pathways specific for AD. We measured 665 proteins in 797 cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment with abnormal amyloid (MCI(Aβ+): n = 50), AD-dementia (n = 230), non-AD dementias (n = 322) and cognitively unimpaired controls (n = 195) using proximity extension-based immunoassays. Here we identified >100 CSF proteins dysregulated in MCI(Aβ+) or AD compared to controls or non-AD dementias. Proteins dysregulated in MCI(Aβ+) were primarily related to protein catabolism, energy metabolism and oxidative stress, whereas those specifically dysregulated in AD dementia were related to cell remodeling, vascular function and immune system. Classification modeling unveiled biomarker panels discriminating clinical groups with high accuracies (area under the curve (AUC): 0.85–0.99), which were translated into custom multiplex assays and validated in external and independent cohorts (AUC: 0.8–0.99). Overall, this study provides novel pathophysiological leads delineating the multifactorial nature of AD and potential biomarker tools for diagnostic settings or clinical trials.