Biomarkers Consortium - Longitudinal Proteomic Changes in CSF from ADNI: Towards Better Defining the Trajectory of Prodromal and Early Alzheimer’s Disease

The lack of tools for early diagnosis and measurement of disease progression in Alzheimer’s disease (AD) continues to be a major hurdle in AD drug development. While developments continue to emerge on hallmark pathologies (Aß, tTau, pTau), the field is still searching for precise measures that can predict clinical trajectories in AD. Of value to drug development are markers that can accurately predict clinical progression from preclinical or early-stages of AD to later stages of the disease, including mild cognitive impairment (MCI) and mild to severe dementia due to AD. Within-subject changes that more accurately predict the progression and rate of change from MCI to AD could be used to better individualize prognosis and plan treatment before irreversible neuropathology.

The Biomarkers Consortium’s Longitudinal CSF Proteomics Project, completed in Q4Y20, was the third stage of a multi-phased effort utilizing samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) expanding on the identification of promising proteins in a previous Biomarkers Consortium project to provide early validation for candidate AD biomarkers. Concentrations of the candidate biomarkers in CSF were measured using a state-of-the-art targeted stable isotope-based quantitative mass spectrometry assay developed and implemented during the first two program stages. 

Goals

  • To measure the absolute quantification of five analytes (NPTX2, VGF, SCG2, CgA and FABP3) that may predict progression from cognitively normal (CN) to (mild cognitive impairment) MCI to AD.
  • To determine if any of the 5 candidate analytes demonstrate a rate of change that would enable their use as supportive endpoints in clinical trials in early AD.
  • To evaluate if intra-individual trajectories of the candidate proteins can be linked to pathological disease progression.

Results and Accomplishments

Additional biomarkers that track pathological processes affecting neuronal function during early stages of AD are needed to more accurately determine whether Alzheimer’s disease pathology (amyloid plaques and tau neurofibrillary tangles) is present, as well as whether and when dementia will develop. The project data indicate that neuronal pentraxin 2 (NPTX2), a mediator of synaptic function, may be such a marker of disease progression in AD, reflecting a process related to cognitive decline. Within-subject NPTX2 rate of change in the CSF showed a robust association with baseline clinical diagnosis of MCI and a positive biomarker profile for AD. NPTX2 decline strongly correlated with cognitive decline even in the absence of greater brain pathology. These findings indicate that NPTX2 concentration changes may serve as not only an early prognostic biomarker of accelerated cognitive decline, but also as a therapeutic target in at least a subset of MCI patients who are diagnosed with AD according to the prevailing β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)] classification. A publication of the project results is in progress. 

Scientific Publications

Libiger, O., Shaw, L.M., Watson, M, Nairn, A., Umana, K., Canet-Aviles, R.M., Jack, C.R., Jr., Breton, Y.,A., Cortes, L., Chelsky, D. Spellman, D., Baker, S., Raghavan, N., Potter, W.Z., Alzheimer’s Disease Neuroimaging Initiative (ADNI), The FNIH Biomarkers Consortium CSF Longitudinal Proteomics Project Team. Identification of NPTX2 as a prognostic biomarker of Alzheimer’s disease through a longitudinal CSF proteomics study in ADNI subjects.
Poster presented at: Alzheimer’s Association International Conference; July 28, 2020; Online.

Data Access

Project data is publicly available on the ADNI Laboratory of Neuroimaging (LONI) website.

Partners

Public-Sector Partners:
National Institute of Mental Health (NIMH)
National Institute on Aging (NIA)
U.S. Food and Drug Administration (FDA)

Private-Sector Partners:
Caprion Biosciences Inc.*
Genentech, a member of the Roche Group*
H. Lundbeck A/S*
Janssen Research & Development, LLC*
Merck*
Takeda Pharmaceutical Company Limited*

Academic Partners:
University of Pennsylvania
Yale School of Medicine

*Provided financial or in-kind support for this program.

FNIH Contact

Erin Rosenbaugh, Ph.D., P.M.P., Associate Scientific Program Manager, Neuroscience; erosenbaugh@fnih.org