Diagnosis of Alzheimer's Disease Genetic testing, imaging techniques, and immunoassayMedical School, Massachusetts General Hospital, and George Washington methods show promise for the biochemical diagnosis University Medical Center has used SPECT to study the muscarinic acetylof Alzheimer's disease choline receptor binding function in an It is estimated that two-and-a-half to three million Americans are afflicted with Alzheimer's disease, a degenerative brain disease that causes progressive loss of memory, language, and reasoning. There is no cure for Alzheimer's disease, although a new experimental drug, tetrahydroaminocrydine, does show promise for reducing memory loss in Alzheimer's victims. As many as 150,000 people are killed by Alzheimer's each year, and the annual cost of caring for these patients has been estimated at more than $12 billion. One of the most troubling aspects of Alzheimer's disease is the fact that it is extremely difficult to diagnose. Physicians must rely on physical examinations and psychological testing to diagnose the disease, and from 20 to 50% of all people who are told they have Alzheimer's actually have some other disease. Absolute confirmation of the diagnosis can only be obtained by microscopic examination of brain tissue for signs of neuronal damage, either through a dangerous brain biopsy or during an autopsy. But research into both the cause and the means of distinguishing Alzheimer's disease from other brain disorders has intensified in the last few years. Research is proceeding in several different directions and includes efforts to identify products of the degenerative process, to detect neurochemical markers such as a decrease in various neurotransmitter levels, and to confirm a possible genetic defect on chromosome 21 that may be implicated in the development of Alzheimer's disease. These research efforts have led to the development of several promising methods for diagnosing Alzheimer's disease, including genetic testing, imaging techniques, and immunoassay methods.
One of the key findings in recent research on Alzheimer's is that the brain tissue of Alzheimer's patients contains distinctive protein tangles that do not appear to exist in normal brain tissue. An international team of neurologists, headed by Ron Polinsky at the National Institute of Neurological and Communicative Disorders and Stroke (Bethesda, Md.), in collaboration with a group of molecular biologists headed by James Gusella at Massachusetts General Hospital, have identified a region of chromosome 21 that appears to be linked with the disease in four fam-
FOCUS ilies that have had Alzheimer's through several generations. A gene responsible for the production of one of the protein tangles also has been located on chromosome 21, leading to the postulation that the cause of Alzheimer's could be at least partially genetic. If further research confirms this genetic link, genetic testing could be used to determine whether a patient showing symptoms of Alzheimer's actually has the disease or has another neurological disorder. Sophisticated imaging techniques that produce pictures of the brain, such as computer axial tomography (CAT scans), positron emission tomography (PET scans), and single-photon emission computed tomography (SPECT), have also been useful in distinguishing Alzheimer's disease from other brain disorders by noninvasively looking for the signs of neuronal damage that are found in postmortem examinations of brain tissue from Alzheimer's patients. For example, a team from Harvard
Alzheimer's patient. Iodine-123 labeled 3-quinuclidinyl-4-iodobenzilate was injected intravenously, and a highresolution, high-sensitivity SPECT instrument was used to produce threedimensional images of the brain. These imaging techniques have the potential of providing a tool for early diagnosis of Alzheimer's cases. But because they are not widely available and are extremely expensive (a complete workup costs approximately $1500), these techniques are not likely to become routine diagnostic tools soon. Immunossay techniques have been used both to determine levels of neurochemical markers in Alzheimer's patients and to detect an Alzheimer's-related protein in cerebral spinal fluid. Researchers at Duke University Medical Center (Durham, N.C.) recently measured the postmortem concentration of the neuropeptide neurotransmitter corticotropin-releasing factor (CRF) by radioimmunoassay in nine brain regions of both control patients and those with histologically confirmed Alzheimer's disease. Compared with tissue from control patients, the Alzheimer's tissue in the latter group shows a marked reduction of CRF concentration in three brain regions, indicating that CRF-containing neurons degenerate in Alzheimer's disease. Previous research has shown that levels of two other neurotransmitters, acetylcholine and somatostatin, are also depressed in Alzheimer's patients. Although all of this work has been done on brain tissue samples, methods that measure CRF, acetylcholine, or somatostatin levels in cerebrospinal fluid could possibly be used as diagnostic tools in the future. Finally, a collaborative effort between researchers at the Institute for Basic Research in Developmental Disabilities (Staten Island, N.Y.), Immuno-Products Industries (Middlesex,
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N.J.), and Senetek PLC (Mountain View, Calif.) has produced an immunoassay for the diagnosis of Alzheimer's disease. The method detects a crossreacting antigen to a monoclonal antibody that was developed from protein tangles extracted from the brain tissue of confirmed Alzheimer's patients. According to John Bennett, president of Senetek, and Howard Rubinstein, president of Immuno-Products, two enzyme-linked immunosorbent assay (ELISA) methods have been developed: a competitive assay and a sandwich assay. Preliminary results indicate that the tests can distinguish Alzheimer's disease from other neurological disorders with about 75% accuracy, which is comparable to the best diagnostic studies using strict clinical and neuropsychological criteria. If these immunoassays can detect Alzheimer's disease earlier than can clinical methods, physicians can then start appropriate treatment for Alzheimer's disease sooner. No cross-reactivity to drugs has been discovered thus far, and the immunoassay method can detect 1-3 ng/mL of the protein antigen in standards derived from the analysis of brain tissue of confirmed Alzheimer's patients. Clinical trials are now underway, and Senetek hopes to start marketing the test in Europe later this year. Plans are also underway to introduce the test in the United States after FDA regulatory requirements have been met. Although Alzheimer's disease was first described by German neurologist Alois Alzheimer in 1907, it has received significant research interest only in the last 20 years or so. In the last 10 years, research on Alzheimer's has increased dramatically with the discovery of biological markers, proteins specific to Alzheimer's disease-afflicted brain tisue, and a possible genetic link. Because most victims of Alzheimer's are elderly (although it has been known to strike in middle age), the number of victims is sure to increase as the elderly population increases. Researchers expect that at least one of the promising lines of recent work on Alzheimer's disease will produce both a reliable diagnostic test and a means of treating the disease. Mary Warner Suggested reading Wurtman, R. J. Sci. Am. January 1985,6274. Ferry, G. New Scientist, Aug. 22,1986,33-5. Edwards, D. D. Science News, Dec. 14,1985, 374-75. Holman, B. L.; Gibson, R. E.; Hill, T. C; Eckelman, W. C; Albert, M.; Reba, R. C. J. Am. Med. Assoc. 1985,254, 3063-66. Bissette, G; Reynold, G. P.; Kilts, C. D.; Widerlov, E.; Nemeroff, C. B. J. Am. Med. Assoc. 1985,254, 3067-69.
