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Originally published March, 1997

IVD Technology News

Test developers pursue early Alzheimer's disease diagnostic

Ask just about anyone in biotechnology about a test for Alzheimer's disease (AD), and you're likely to hear about its revenue-generating potential. Even modest estimates put the market for a reliable diagnostic for AD in the realm of $200 million annually.

But if it were as easy as winner-take-all, Athena Neurosciences, Inc. (South San Francisco), would be in the catbird seat. The company's ADmark assays--whose introduction for investigative use only last March was followed by supportive studies in key scientific journals--were the first on the scene (Lancet, 348:90­93, 1996). They have received the kind of headline press coverage usually reserved for a breakthrough drug treatment. Similar reports followed more recent announcements of competing Alzheimer's tests: a blood screen that detects metabolic changes associated with onset of disease (MitoKor, San Diego) and a test that measures the concentration of a key brain protein in spinal fluid (Nymox Corp., Rockville, MD).

Then why has the fanfare been so short-lived? Because some physicians in Alzheimer's research don't yet endorse this kind of testing. Last fall, the Agency for Health Care Policy and Research, an office in the Department of Health and Human Services, weighed in with guidelines for early recognition of the disease. The guidelines, representing a consensus of scientists at centers across the country, concluded that no test "has a high sensitivity for early or mild dementia." They advise physicians and HMOs that "no evidence supports the efficacy of a general screen for Alzheimer's."

Though the government's panel of experts did not take aim specifically at the new marker-based tests, Robert Davis, PhD, president and chief scientific officer at MitoKor, notes that endorsement by the medical community now is nearly as important to the success of a new test as FDA approval is. An FDA okay has gone from cause for celebration to reason for "optimism," he adds. The actual success of any of these tests will depend on "getting geriatricians and neurologists on board.

"In cases like this, you want to be able to spend a lot of time educating both physicians and the public," Davis stresses. MitoKor's assay detects mutations in mitochondrial genes encoding for cytochrome oxidase, an enzyme complex that is associated with the kind of defective brain metabolism that coincides with the onset of Alzheimer's. Soumitra Ghosh, PhD, who has been a major contributor to much of the groundbreaking work that is being done at MitoKor, says the company plans to move slowly to allow adequate time for validation. MitoKor's test is now being used primarily for research. When an application is made to FDA in 18 months or so, "we need to be able to say 'this indeed is confirmatory for diagnosis,' " says Ghosh.

The Nymox test, dubbed "AD7C," measures the concentration in cerebrospinal fluid of a brain protein, AD7C-NTP (a neural thread protein), that, according to research, is found in higher-than-normal concentrations in Alzheimer's patients.

"This test is as good as postmortem diagnosis, which is at present the gold standard," says Hossein Ghanbari, PhD, Nymox's senior vice president for research and development. Nymox has completed the requisite clinical studies and is putting together a premarket approval (PMA) application for test kits that could be sold to other reference laboratories. "In the future, we want to be partnering with companies that have automated systems," Ghanbari adds.

Most physicians recommend using current IVDs only as a second-tier confirmation of clinical observations. Allen Roses, MD, a scientist at Duke University (Durham, NC), developed the first genetic screen for AD; it is now licensed to Athena. Roses, whose work has been replicated by other centers, demonstrated that the presence of a certain genotype of ApoE, E4/E4, increases the probability of development of AD to over 90%. But he has repeatedly stressed that there are significant "drawbacks" to depending on a stand-alone test--at least so far. As Eric Liebler, director of external communications for Athena, puts it: "Physicians are still more comfortable with doing a CAT scan" in the wake of positive findings.

The Athena ADmark assays actually are two tests, not one. They detect not only ApoE but also the tau and beta-amyloid proteins. The ApoE, which is currently a blood test, may become a cheek-swab test by next fall. The protein tests use cerebrospinal fluid.

The search for a dependable marker for Alzheimer's has lasted two decades, since autopsy studies were first used to demonstrate definitive differences between the brains of patients with AD and normal brains. Now the characteristic tangles of nerves in the brain, as well as the gradual reduction in overall brain size, can be detected on imaging studies long before death occurs. Still, AD--which is believed to be responsible for the majority of dementia--continues to elude investigators bent on catching it in the early stages, when therapies recently described, like the newly approved drug Aricept, show their highest efficacy. Recent reports indicate that estrogen replacement therapy in women, when it is started early enough, may mitigate the disease as well.

In one of the largest studies on dementia that have been done to date, a group of Canadian researchers evaluated the consistency of diagnoses in several thousand patients across the provinces of their country (Neuroepidemiol, 15:246­256, 1996). Their findings indicated a sore lack of standardization of diagnostic procedures and clinical evaluations for assessment of cognitive impairment.

The study was published about the same time U.S. government figures regarding dementia were issued. Nearly $90 billion is spent annually in the United States on Alzheimer's alone, according to the National Institute on Aging. An estimated 5­10% of American adults over 65 are affected by some form of dementia, and the incidence is believed to double with every additional five years of age among this group, federal investigators warned.--Anne Scheck