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More tools for Alzheimer's diagnosis on the way
According to the National Institutes of Health, Alzheimer's disease (AD) is the most overdiagnosed and misdiagnosed mental-function disorder among older adults in the United States. The disease is difficult to isolate because it is one of more than 70 conditions that cause dementia. Currently, AD can be confirmed only by a postmortem examination of the brain.
Although the field is wide open for companies working on accurate biochemical technologies for early diagnosis of AD, progress has so far been slow. "Among the many proposed molecular and biochemical markers, none has yet achieved universal acceptance or fully met the proposed criteria for an ideal biomarker," according to a consensus report on molecular and biochemical markers of AD prepared by the National Institute on Aging and the Ronald and Nancy Reagan Research Institute of the Alzheimer's Association.
At least three companies have jumped into the race—each exploring a different set of markers. Mitokor (San Diego) is investigating the use of changes in mitochondrial DNA as a marker for AD. Nymox Corp. (St.-Laurent, PQ, Canada) says that an elevated level of neural thread protein (NTP) is indicative of AD. And Athena Diagnostics (Worcester, MA) has developed a genotyping test, a test for biological markers, and a gene-sequencing test for AD.
Until the clinical accuracy of such markers is demonstrated, clinicians and their patients must make do with the current method for diagnosing AD, which is often referred to as a diagnosis of elimination. That process is both complex and expensive, involving a wide range of tests. The physician asks the patient or caregiver to provide a history and progression of symptoms, and may also make use of psychological studies and tests of the patient's sensation, cognition, and motor functions. The physician may order a head CT scan, x-ray, or magnetic resonance imaging (MRI) to determine if the patient shows signs of atrophy or other changes in the white matter of the brain. And an electroencephalograph (EEG) may be used to document nonspecific changes in the brain.
Even with the results of all these tests taken together, the current method still only enables the physician to diagnose the patient's condition as "probable" AD. According to the Alzheimer's Association, the method is 80 to 90% accurate—but there are some significant drawbacks. By the time the diagnosis is made, the patient has undergone a multitude of tests at considerable cost and discomfort. More important, by the time every test has been done and every other disorder eliminated, the patient may have already experienced significant impairment in brain function, thereby limiting treatment options.
"It is increasingly important to have this disease recognized early because there are medications now available that keep people functioning at a higher level for a longer period of time," says Debra Cherry, PhD, associate executive director of the Alzheimer's Association of Los Angeles. "Also, the earlier they know their diagnosis, the more time patients will have to participate with their families in healthcare, financial, legal, and other plans for the future." An early and accurate diagnosis can also rule out AD in patients with other types of dementia or medical conditions, so that physicians can treat or cure those diseases before the damage becomes irreversible.
Among the companies in the search for an AD diagnostic, Mitokor is focusing on genetic changes in the mitochondria. "What we find is that in some cases the ratio of nuclear DNA to mitochondrial DNA increases with Alzheimer's disease," says Michele LeGear, Mitokor's vice president for corporate development. The company has developed the Mitoload assay, a blood-based in vitro nucleic acid test that measures quantitative changes in mitochondrial DNA. Although LeGear admits that the company has a long way to go in studying its assay, it is certain that "there is a high correlation between mitochondrial defects and neurological diseases."
To validate the Mitoload assay, the company has conducted clinical trials with more than 1000 symptomatic late-onset AD patients compared with age-matched control patients. To stratify subjects into subpopulations for clinical assessment and subsequent treatment, a further trial involving more than 2000 patients is now under way. And the company has recently entered into a collaboration with SRL (Tokyo), Japan's largest clinical testing laboratory, to use the Mitoload assay and software for diagnosing AD and selecting candidates for clinical trials.
Meanwhile, Nymox Corp. is following up on research suggesting that elevated levels of neural thread protein (NTP) in the brain indicate the presence of AD. "There is evidence that this protein promotes neurodegeneration," says Jack Gemmell, media relations staffer for Nymox. The company has developed an immunoassay that detects NTP in both cerebrospinal fluid (CSF) and urine. "The test is performed in a CLIA-certified laboratory and has proved to be a highly reliable and accurate measure of NTP levels," says Gemmell.
According to the company, its CSF test has a sensitivity of 89% and specificity of 89%; the urine test is 80 to 85% sensitive and more than 90% specific.
Athena Diagnostics is looking at genetics to diagnose AD. "Patients with the E4 allele located on chromosome 19 are more likely to develop Alzheimer's disease," says Athena product manager Dave Hanak. Athena's Admark ApoE geneotype analysis and interpretation system uses a blood sample. The test identifies the patient's ApoE genotype. According to the company, in patients with dementia the presence of one or more E4 alleles confirms the presence of AD.
"The test has a 94 to 98% positive predictive value," says Hanak. For those patients whose results are inconclusive, the company offers an additional test. The Admark Tau/AB42 CSF analysis and interpretation test measures the levels of tau protein and amyloid beta 42 in cerebrospinal fluid. Company researchers believe that high levels of tau combined with low levels of AB42 are indicators of AD, while low levels of tau and high levels of AB42 indicate another cause of dementia. The test has a sensitivity of 70% and specificity in the low 90% range. According to the company, the combination of these two assays provides a diagnostic result 92% of the time.
Athena also offers the Admark PS-1 analysis and interpretation system for diagnosis of early onset familial AD. The system sequences the entire coding region of the presenilin-1 gene on chromosome 14 and reports mutations as a positive result. According to the Reagan Institute report these mutations are the most common cause of this rare type of AD. The report says "finding a mutation in the PS-1 or APP gene has a high predictive value (presumed to be 100%) for the eventual development of AD." The consensus report concludes that analyses of the PS-1, PS-2, and APP genes are appropriate as an adjunct to diagnosing dementia in patients with an early age of onset and a strong family history of AD.
Despite researchers' success with the presenilin-1 test, experts agree that a great deal more research will be required before all forms of AD can be diagnosed conclusively in the living. The tests now being developed cannot yet be used as stand-alone diagnostics for AD, but they may prove useful for gathering more evidence to support current diagnostic methods.—Susan Wallace
