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

Accelerating the ability to predict, diagnose and treat Alzheimer’s disease

The Problem
Alzheimer’s disease (AD) researchers lack the tools needed to diagnose pre-symptomatic and early disease, and to predict how/at what rate a patient’s AD is likely to progress – limitations that hinder AD drug development and clinical care.
The Solution
This project assessed whether measuring levels of promising proteins in AD patients may enable diagnosis of early AD and prediction of disease progression: identifying a predictive protein marker called NPTX2.

Overview

The lack of tools for early diagnosis and measurement of disease progression in Alzheimer’s disease (AD) constitutes a major hurdle for AD drug development. While researchers work to identify hallmark pathologies of AD (Aß, tTau, pTau), the field continues to search for precise measures that can predict clinical trajectories of the disease. Successful efforts to develop drugs for AD require biomarkers that can accurately predict clinical progression from preclinical or early-stages of AD to later stages of the disease, including AD-related mild cognitive impairment (MCI) and mild-to-severe dementia. Identifying within-subject changes that can be used to accurately predict a patient’s progression and rate of change from MCI to AD could be used to individualize patients’ prognosis and thus their treatment plans, before development of irreversible neuropathology.

The Biomarkers Consortium’s Longitudinal CSF Proteomics Project, completed in 2021, was the third stage of a multi-phased program that used samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This third stage provided early validation for proteins identified by a previous Biomarkers Consortium project that show potential promise as candidate AD progression biomarkers. Cerebrospinal fluid (CSF) concentrations of the candidate biomarkers were measured using a state-of-the-art quantitative mass spectrometry assay, which was developed and implemented during the first two program stages.

Goals

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

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 & Co., Inc.*
  • 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

Results & 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. 

Identification of NPTX2 As a Potential Marker of AD Progression

The project data showed that the CSF concentration of NPTX2, a mediator of synaptic function, exhibited rates of change that significantly differed between CN and MCI subjects as well as p-Tau181/Aβ1-42 ratio positive and negative subjects. Decreasing CSF NPTX2 levels correlated with declining cognitive function, even in the absence of greater brain pathology. These findings indicate that changes in CSF NPTX2 could serve not only as an early prognostic biomarker of accelerated cognitive decline, but also as a potential pharmacodynamic biomarker.

Scientific Publications

Data Access

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