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CSF Biomarkers and the advancement of Alzheimer's Disease Trials

CSF biomarkers & Alzheimer's Disease

The Use of CSF Biomarkers in Alzheimer's Clinical Trials

The Importance of Early Diagnosis for AD
Last month, scientists, clinicians, drug sponsors, and regulators gathered in our nation's capital at the annual Alzheimer's Association International Conference (AAIC) to share recent advances in AD research and clinical drug development. One of the biggest challenges facing the AD research community is the ability to identify patients early in the disease process, before the onset of clinical symptoms. Identifying such populations for early intervention will maximize the likelihood of advancing successful drug candidates.

To do this, we need a better understanding of early mechanisms and predictors of AD. The development of imaging tracers and cerebrospinal fluid (CSF) biomarkers has facilitated the discovery of long preclinical stages of disease and has helped define a spectrum of disease states ranging from asymptomatic (preclinical), to a prodromal symptomatic stage (mild cognitive impairment, MCI), to a symptomatic stage characterized by dementia.

Individuals in the preclinical stage are receiving intense focus as a targeted population for trials aimed at identifying disease-modifying therapies which can preserve cognitive function. As a result, biomarkers are being evaluated for their diagnostic and prognostic utility in patient cohorts.

The rise of CSF biomarkers
Given that CSF is in direct contact with the extracellular space of the brain, it is considered a prime source for AD biomarker discovery. Currently, several protein biomarkers that can be found and quantified in CSF, including Aβ1-42 and total Tau reflect core neuropathologies. Studies of these CSF biomarkers reveal important correlations with AD disease. Aβ1-42 is a peptide that comprises the main component of amyloid plaques. Studies have shown that concentrations of Aβ1-42 in post mortem CSF correlate inversely with plaque load at autopsy and in living persons by PET amyloid imaging. Tau is a microtubule stabilizing protein that is the primary component of neurofibrillary tangles in AD. CSF Tau (and its phosphoisoforms) are consistently elevated in conditions of robust neuronal cell death including AD, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Creutzfeldt Jakob disease (CJD).

There is a tremendous effort underway to evaluate the prognostic and diagnostic performance of CSF biomarkers throughout the continuum of disease progression. Reflecting our understanding of disease, new criteria that incorporate biomarkers for identifying different stages of AD have recently been proposed by several working groups convened by the National Institute on Aging-Alzheimer's Association (NIA-AA).

The use of CSF biomarkers in Clinical Trials
Biomarker characterization over the normal course of the disease is being used to inform the design of clinical trials and the evaluation of efficacy of new disease modifying therapies. CSF biomarkers of AD are being used in current and planned trials to enrich patients, stratify patients, and monitor efficacy after treatment. As with other biomarkers and companion diagnostics, CSF biomarkers have the potential to reduce patient numbers, trial costs, and trial duration and help with go/no go decisions in advancing promising candidates. There is also a growing interest in ultimately using biomarkers as surrogate endpoints for accelerated approval of drug candidates. Achieving these goals will require 1) validation of CSF biomarkers in large well characterized research cohorts (which are evaluated for AD related covariates) 2) protocol and assay standardization to maximize specificity, sensitivity and reliability of CSF biomarkers (within and between laboratories), and 3) establishing cutoff points and thresholds to define biomarker positivity.

Biomarker standardization efforts are already underway to develop commercial assay platforms with high throughput capability. Efforts to obtain FDA approval for the use of CSF biomarkers in US clinical settings are also underway. A letter of support from the Center for Drug Evaluation and Research (CDER) was issued earlier this year to the Coalition Against Major Diseases (CAMD) to encourage the further study of CSF biomarkers as exploratory prognostic biomarkers for enrichment in AD trials. The letter further emphasizes the application of good laboratory practices and the standardization of assay methodologies to improve reproducibility and reliability in ongoing clinical trials.

Aligned with these efforts, BioClinica Lab is working to establish an efficient, quality-driven, fit-for-purpose assay using CSF biomarkers for patient enrichment in clinical trials. To this end, we have recently completed a comprehensive evaluation of Aβ1-40, Aβ1-42, and total Tau assays using CSF samples from healthy individuals which monitored key analytical features including precision, dilution linearity, spike-recovery, working range in CSF, and sample stability. We are pleased to have shared the results of our validation studies at this year's AAIC meeting and are excited to be contributing to the growing and important field of CSF biomarker development.


  1. alzheimer report 2010.pdf
  3. Fagan A. CSF Biomarkers of Alzheimer's Disease: Impact on Disease Concept, Diagnosis, and Clinical Trial Design. Advances in Geriatrics. 2014.

Fit-for-Purpose Validation of the Cerebrospinal Fluid Markers Aβ1-40, Aβ1-42 and Total Tau


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