Scientists Detail New Early Test for Alzheimer’s

Southern California scientists report they have developed the first test that appears to be able to detect Alzheimer’s disease in its early stages.

Such early diagnosis would allow prospective Alzheimer’s victims to plan for their care and make arrangements for their families while they are in control of their mental faculties.

In the longer term, when new drugs for Alzheimer’s become available, such diagnosis might make it possible to treat victims at the beginning of the debilitating disease when chances of success are higher.

Now, it is very difficult to diagnose Alzheimer’s, which affects as many as 4 million Americans. Physicians typically identify it by the elimination of other possibilities, but in doing so misdiagnose 10% to 20% of patients, according to the Alzheimer’s Assn. The disorder can be confirmed definitively only by examining the brain in an autopsy.

Researchers at SIBIA, a La Jolla-based biotechnology offshoot of the Salk Institute, report their success in using the new test in an Indiana family with hereditary Alzheimer’s disease. The researchers write in today’s issue of The Lancet that the new test correctly identified members of the family who carry a gene that produces the disorder.

Even more promising, the test was able to show that one family member with no apparent symptoms is developing the disease. A subsequent neurological examination confirmed that diagnosis.

Successful studies with the test in about 100 human patients have been reported by researchers using the SIBIA test. The Lancet study reported today is particularly significant, even though it covers only six people, because of what it shows about the ability of the test to chart the progress of the disease, said biochemist Steven L. Wagner of SIBIA.

Studies on much larger numbers of patients are in progress at Alzheimer’s centers around the country. If those results are as successful as the preliminary studies, the company will begin marketing the test next year, Wagner said.

While larger numbers of patients will have to be studied, the new test looks promising, said Dr. Creighton Phelps, a neurologist at the National Institute of Aging in Bethesda, Md. “An earlier diagnostic test will be very useful as we develop treatments that might slow down the course of the disease. . . . We’re hoping we’ll have such treatments in the next couple of years. If we could just delay the onset of the disease by even five years, the quality of the patient’s life would be much enhanced.”

Alzheimer’s disease is characterized by a progressive and irreversible loss of memory and thought processes. It is the most common cause of dementia and is primarily a disease of the elderly, afflicting 5% to 10% of the population over 65.

The distinguishing mark of Alzheimer’s is the accumulation in the brain of deposits, called plaques, of a substance called amyloid beta-protein. Studies in animals have shown that accumulation of these plaques destroys brain cells and impairs brain function.

The amyloid beta-protein is an abnormal product formed from a larger compound called amyloid precursor protein or APP. It is this protein that SIBIA looks for in the cerebrospinal fluid of patients.

Several studies have shown that at least some forms of familial Alzheimer’s disease are caused by a specific mutation in the APP gene, and many researchers believe that most cases of the disorder are caused by a spectrum of APP abnormalities.

If that is the case, Wagner and molecular biologist William E. Van Nostrand of UC Irvine reasoned, there should be less of the healthy APP in the cerebrospinal fluid of Alzheimer’s victims. They developed an antibody test for APP and began looking at patients.

In general, they found that the APP level in Alzheimer’s victims was less than one-third as high as in healthy individuals.

In the current study, three of the six family members do not carry the Alzheimer’s gene and all three had normal levels of APP in their cerebrospinal fluid. One member with the gene had a severe form of the disorder and had very low concentrations of APP.

But the most interesting finding involved the two family members who carried the gene but did not appear to have any symptoms. One was in his early 30s and had normal levels of APP. The second was in his late 30s, much closer to the age at which the family members typically develop the disease. His APP levels were intermediate between those of the normal and affected family members.

When neurologists re-examined this patient, they found that he did have some impairment in verbal and visual recent memory, information processing and conceptual reasoning. “But this individual would not meet the criteria for a clinical diagnosis of Alzheimer’s disease,” Wagner said.

“What we think is going to come out of this study is that, when patients have severe pathological changes, we’re going to be able to pick them up before they become severely demented,” he said.

Although there is nothing that can be done for such patients, the information could prove useful. “If it’s going to afflict the breadwinner in the family, people might want to know,” he said.