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Study boosts confidence in potential screening tool for Alzheimer's disease
A major study has confirmed the value of potential markers for identifying people with Alzheimer's disease. Scientists at the National Institute of Mental Health (NIMH) found that levels of two key indicators in spinal fluid distinguished clinically diagnosed Alzheimer's patients from controls with 89-92 percent efficiency. This matches or exceeds current clinical diagnostic methods, such as doctor's evaluation of medical history, cognitive testing, and brain scans. However, the potential telltale signs, or biomarkers, won’t be ready for use as predictive and diagnostic tools until completion of long-term studies now underway. Trey Sunderland, M.D., Chief, NIMH Geriatric Psychiatry Branch, and colleagues, report on their study -- which included both direct examination of 203 patients and controls and a meta-analysis of world literature -- in the April 23, 2003 Journal of the American Medical Association.
“We’re hopeful that biomarkers will eventually be developed to help detect incipient illness in younger people who are at risk but who may not yet show any symptoms,” said Sunderland. “Clues from biochemical, genetic and brain imaging studies could point to new possibilities for preventive interventions.”
The NIMH study examined cerebrospinal fluid (CSF) levels of two protein fragments, hallmarks of the disease process, found in brains of Alzheimer’s victims: beta-amyloid, which clumps together to form brain-damaging plaques, and tau, which strangles neurons in tangled filaments. Like many previous studies, it found that CSF beta amyloid levels drop, while tau levels rise in Alzheimer's. What’s new is that the confidence level in this finding has now been boosted by applying a meta-analysis of the world literature and adding “ the largest cohort of Alzheimer’s disease patients and controls evaluated to date,” say the researchers.
To gather their data, Sunderland and colleagues performed spinal taps on 131 Alzheimer's patients and 72 control subjects and measured CSF levels of the suspect protein fragments. As the fluid that bathes the brain, CSF has long been considered the most reliable window available into a living human’s neurochemical activity. Beta-amyloid levels in Alzheimer’s patients averaged only 183 picograms per milliliter of CSF, compared to 491 in controls. Patients’ tau levels dwarfed controls 587 to 224 picograms per milliliter. These differences remained significant even after statistical analysis controlled for effects of age and sex. Taken together the two markers distinguished clinically diagnosed Alzheimer’s patients from controls with a sensitivity of 92 percent and a specificity of 89 percent.
Years of education were associated with lower CSF tau levels among Alzheimer’s patients, suggesting a possible protective factor. Evidence suggests that the changes in beta-amyloid and tau levels may be present early in the disease process.
The researchers also performed a meta-analysis of 51 similar studies, totaling 3133 Alzheimer's patients and 1481 controls. These included 17 controlled studies of beta-amyloid winnowed from 188 articles, and 34 studies of tau, sifted from an initial list of 200 articles. Of the beta-amyloid studies, 14 of the 17 found the same pattern seen in the NIMH sample. All of the tau studies showed the same pattern as the NIMH sample.
However, for both measures, the researchers found considerable overlap in levels between the Alzheimer’s and control groups. “It is evident that the diagnostic sensitivity and specificity of these individual CSF beta-amyloid and tau assays is simply not sufficient to warrant general clinical use of these biomarkers for individual use,” they caution. They call for additional studies to standardize assay methodology, and for “real world” comparisons between Alzheimer’s patients and people with other forms of dementia, noting that these would likely show even more overlap.
“Perhaps the most important future use for such biomarkers is in the prospective study of people at risk for developing Alzheimer’s disease,” noted Sunderland. “By establishing a person’s baseline and tracking levels over time, we might be able to interpret gradual changes as a sign that he or she is developing the disorder.”
Also participating in the research were: Robert M. Cohen, M.D., Ph.D., Gary Linker, M.D., Nadeem Mirza, M.D., Karen Putnam, Judy Bergeson, M.A, Guy Manetti, Matthew Zimmerman, Brian Tang, NIMH; David Friedman, Ph.D., Lida Kimmel, M.S., Pfizer Pharmaceuticals; John Bartko, Ph.D., consultant statistician.