Two biomarkers found in cerebrospinal fluid – tau and beta-amyloid proteins – may be the key to diagnosing the early stages of Alzheimer's disease sooner and more accurately, according to a new report. Researchers from the Alzheimer's Disease Neuroimaging Initiative (ADNI) not only confirmed that certain changes in biomarker levels in cerebrospinal fluid may signal the onset of mild Alzheimer's, but also established a method and standard of testing for these biomarkers.
"I think it's too early to say how early we really can identify changes," Neil Buckholtz, PhD, of the National Institute on Aging's Division of Neuroscience (NIA; Bethesda, Maryland), told Diagnostics & Imaging Week. But, he said, this methodology in conjunction with other methods – such as neuroimaging and genetic factors – could eventually give clinicians a way of identifying the disease "very early."
ADNI is a research partnership supported primarily by the NIA, part of the National Institutes of Health, with private-sector support through the Foundation for NIH, seeking to find neuroimaging and biomarker tests that can detect Alzheimer's disease progression and measure the effectiveness of potential therapies.
These are the first cerebrospinal fluid biomarker findings to be reported by ADNI, a $60-million, five-year research program launched in 2004 to observe and track changes in some 800 older people in the U.S. and Canada with normal cognition, mild cognitive impairment (MCI) – a condition that often precedes Alzheimer's – or the early stages of Alzheimer's.
The ADNI Biomarker Core at the University of Pennsylvania School of Medicine (Philadelphia), headed by Leslie Shaw, PhD, and John Trojanowski, MD, PhD, led the study, which was reported online March 17 in the Annals of Neurology.
"Research indicates that Alzheimer's pathology causes changes in the brain some 10 to 20 years before any symptoms appear," said NIA Director Richard Hodes, MD. "This work gives researchers a systematic and reliable method to measure changes in cerebrospinal fluid biomarkers that may herald the onset of Alzheimer's disease. More research is needed to validate these findings, but this study takes us one step closer to providing researchers and clinicians with tools to detect and understand the very early signs of the disease."
The researchers collected cerebrospinal fluid from 410 ADNI volunteers at 56 different sites, tested the samples for the tau and beta-amyloid protein biomarkers associated with Alzheimer's pathology, and then retested the volunteers a year later to track changes in cognition. The scientists also compared the ADNI cerebrospinal fluid samples to those collected from an independent group of 56 people who were later confirmed in autopsy to have had Alzheimer's and from 52 older people with normal cognition.
This comprehensive analysis allowed the scientists to systematically confirm earlier studies on cerebrospinal fluid findings and to develop biomarker profiles that may signal the onset of the disease.
Among their findings:
• Levels of beta-amyloid protein, in particular beta-amyloid 1-42, were lower among ADNI volunteers with MCI compared to those with normal cognition, and lower still among those diagnosed with mild Alzheimer's disease. Decreased levels of this biomarker in the cerebrospinal fluid may indicate that this least soluble form of amyloid is forming sticky plaques between neurons, a hallmark of Alzheimer's.
• Levels of beta-amyloid 1-42 proved to be the most sensitive biomarker, with an overall test accuracy rate of 87% in detecting Alzheimer's pathology in the ADNI volunteers and in people with autopsy-confirmed Alzheimer's.
• Levels of tau were higher among ADNI volunteers with MCI than among people with normal cognition, and even higher among the volunteers diagnosed with mild Alzheimer's disease. Tau, a protein released by damaged and dying brain cells, can form tangles within cells and may prevent neurons from communicating with each other.
In addition to cerebrospinal fluid biomarkers levels, the researchers factored in a known genetic risk factor for Alzheimer's disease – the gene APOE-e4 – into their analysis. The gene occurs in about 40% of all people who develop Alzheimer's at age 65 or later, but how it increases risk is not yet known. ADNI volunteers with APOE-e4 genes, high levels of tau and low levels of amyloid were most likely to have mild Alzheimer's.
"I think eventually all of those things are going to allow us to identify people earlier," Buckholtz said. "The critical thing is to follow all these people to see what actually happens."
The scientists noted that all 37 ADNI volunteers diagnosed with MCI at the start of the study were documented as having probable Alzheimer's disease a year later. That conversion could be predicted by their cerebrospinal fluid biomarkers, since their baseline profiles were similar to ADNI volunteers already diagnosed with the disease. Conversely, three ADNI volunteers with MCI at the start of the study, but whose cerebrospinal fluid biomarker levels were similar to volunteers free of the disease, reverted back to normal cognition by the end of the study.
"This effort may open the door to the discovery of an entire panel of cerebrospinal fluid biomarkers that will not only predict those at risk of developing Alzheimer's disease, but also reveal how the disease is responding to therapies," Buckholtz said. "Like all ADNI results, these findings have been posted to a publicly accessible database available to qualified researchers worldwide."
To date, more than 800 researchers have signed up for ADNI database access. In addition, qualified scientists may also ask for access to the cerebrospinal fluid and blood samples.
"What we really wanted to do was set up a way that people can access the database [and] do the kinds of analyses that they're interested in," Buckholtz said.
In addition to the NIA, the ADNI public-private partnership includes federal support from the National Institute for Biomedical Imaging and Bioengineering, also part of NIH, and the participation of the FDA. Private-sector support comes from pharmaceutical companies and other organizations through the Foundation for NIH, which has raised more than $25 million from both corporations and non-profits toward ADNI.