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See Inside July/August 2009

Alternative Ideas about Alzheimer's

What if the characteristic plaque in the brain does not actually cause the disease?

With dementia, Alzheimer’s disease brings amyloid plaques—proteins that accumulate in the brain. Many scientists believe the plaques are responsible for gradually destroying memory and brain functions. Most research—and most attempts at early diagnosis and treatment—depends on that supposition being correct. But new imaging technologies, which can show plaque buildups in the brains of living subjects, have produced a paradox: some people with plaque remain cognitively intact. A small minority of researchers think this finding suggests a different culprit behind Alzheimer’s: oxidative stress.

About 10 to 40 percent of cognitively intact people have been shown to have the same amyloid plaques found in autopsies of Alzheimer’s patients but show no signs of the disease. That observation raises two possibilities: either the disorder grows so slowly that these people are just in an early phase of the disease and eventually will show symptoms, or the accepted theory is wrong. Most researchers are convinced it is the former—Alz­heimer’s can take a decade to grow to severity. That belief is based on years of research, but the way the disease progresses still has not been nailed down, because until now the only way to definitively diagnose Alzheimer’s (as opposed to other kinds of dementia) was by an autopsy after the patient had died.

One puzzling study at the University of California, Berkeley, revealed in November 2008 that Alzheimer’s patients, on average, did have higher levels of amyloid than normal controls, but there was overlap. Some of the controls had more amyloid than some patients yet showed none of the symptoms of Alz­heimer’s. Other studies, including research at Harvard Uni­versity, reported in December 2008, did uncover a slight decline in memory in cognitively intact subjects with amyloid buildup over time. The Harvard study lasted only one year, however, and the changes in memory were slight. One type of memory decline was related to an increase in amyloid, but correlation alone does not imply causation—again, ambiguous results.

If the amyloid does not cause Alzheimer’s, what does? Dis­senters to the accepted paradigm think it may be oxidative stress, the wear and tear caused when the body cannot dispose of excess reactive oxygen, which damages cells. The process happens normally as we age. In this theory, the amyloid buildup is more a result of the disease than the cause. Mark A. Smith, a pathologist at Case Western Reserve University and a leading proponent of the oxidative stress theory, says that almost all 80-year-olds have the pathology of Alzheimer’s—plaque and tangles—but most of these seniors do not have the disease. A 50-year-old with Alzheimer’s might have less amyloid than an 80-year-old without symptoms. “If you are 50 and have five plaques and five tangles, you probably have Alzheimer’s,” he says. “If you are 70, you need significantly more” for a diagnosis. Smith thinks the amy­loid and tangles may be scarring caused by the disease or the body’s way of compensating for the oxidative stress—an expla­nation, he confesses, that is “heresy” to most of his colleagues.

Data confirm that Alzheimer’s patients show signs of oxidative stress. If the alternative hypothesis is borne out, antioxidants such as vitamins C and E at least ought to slow the progression of the disease. The only test to date, in which subjects were given vitamin E, failed to show any positive results. Smith points out, however, that the researchers may not have used enough of the vitamin, which is not a particularly good antioxidant and did not lower oxidative stress in the study. Another possibility, he admits, is that the oxidation theory is wrong. Smith thinks the jury is still out, but he urges his colleagues following the amyloid theory to keep at it: “I could be wrong.”

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