Delaying Dementia

Drugs that fail as cures might still prevent Alzheimer's disease

Alzheimer’s disease extinguishes the mind and body through a vicious progression from mental lapses, memory loss, and dementia to the final failure of the brain to support survival. Medical efforts to abate the disorder’s development after symptoms arise have yielded discouraging results. Once unmistakable traits of Alzheimer’s emerge, it seems, the mind is at the disease’s scant mercy. None of the five drugs with U.S. government approval for Alzheimer’s, including the latest, called memantine or Namenda, does more than slow or temporarily stop mental deterioration.

BRIGHT SPOTS. Deposits of beta-amyloid are indicated as red and yellow in brain scan images (left) from different perspectives in a person with Alzheimer’s disease. A healthy brain (right) is shown cool blue. With scanning techniques, physicians can now reliably diagnose full-blown Alzheimer’s disease but not its earliest manifestations. W.E. Klunk & C.A. Mathis/Univ. of Pittsburgh

Meanwhile, increases in life expectancy and a burgeoning population of elderly people are expanding the scope of the Alzheimer’s problem. While some 4 million people in the United States have the disease now, 13 million could have it in 2050.

To avert the rising tide of Alzheimer’s in the absence of a cure, many researchers are looking to drugs and nutrients that could prevent or at least delay the disease’s onset. Marginally delaying the average onset of Alzheimer’s could take a substantial bite out of the epidemic, says Carl W. Cotman of the University of California, Irvine. He estimates that pushing back initial symptoms by 5 years in the average Alzheimer’s victim would halve the number of new cases that appear yearly in the U.S. population.

Recent advances in brain imaging have increased the reliability of diagnosing full-blown Alzheimer’s in a living person. But the brain’s biology begins to go haywire long before symptoms of serious mental decline or outright Alzheimer’s become evident. And it’s still a challenge to distinguish someone on track to developing Alzheimer’s from someone who is aging normally—much less treating that individual to slow or stop the disease process.

Epidemiological observations have generated promising leads to preventive treatments, including statins, antioxidant compounds, anti-inflammatory drugs, and, for women, female sex hormones.

The approaches might be especially valuable to people with mild cognitive impairment, which is characterized by mental deficits such as repeated failure to remember an important detail that are somewhat more severe than those associated with normal aging. About half of people of all ages with mild cognitive impairment develop Alzheimer’s disease within 3 to 5 years. This trait can appear before a person exhibits the physical change diagnostic of Alzheimer’s disease: the buildup in the brain of plaques of proteins called beta-amyloid peptides.

Beta-amyloid deposits appear to trigger inflammation and cell death.

But attempts to treat Alzheimer’s disease with the treatments under consideration have generated either negative or conflicting results. Researchers now hypothesize that at least some of these approaches may have value only if they are administered years before cognitive decline becomes evident. Once an appointment with Alzheimer’s approaches, it may be too late to cancel or reschedule.

Statin static

Some researchers consider statins, the much-touted cholesterol-lowering drugs, a beacon of hope for Alzheimer’s prevention and treatment. Epidemiological studies published in 2000 first indicated that the drugs might lower a person’s lifetime risk of developing the disease by as much as 70 percent. Physiological research bolsters that possibility, in that beta-amyloid appears to build up only in the presence of cholesterol, which statins may draw out of the brain.

Furthermore, some recent research indicates that statins can attenuate the accumulation of beta-amyloid in the brains of mice that are genetically engineered to develop the plaques.

While no trial on people has yet tested whether statins prevent Alzheimer’s, several research groups are examining whether the drugs can ameliorate visible signs of the disease. They’ve had mixed results, but the latest data give some cause for optimism. At a scientific meeting in Montreal on April 17, D. Larry

Sparks of the Sun Health Research Institute in Sun City, Ariz., reported that atorvastatin, which manufacturer Pfizer calls Lipitor, stopped or reversed mental decline in two-thirds of volunteers with Alzheimer’s who took the drug for a year.

“I have a smile on my face,” he says. “This is truly exciting news.”

The Pfizer-supported study included only 63 people, and its results are preliminary. Data from a larger trial due out later this year will be pivotal in determining whether statins work consistently in treating Alzheimer’s.

In Alzheimer’s research, exciting leads have a habit of withering away.

Antioxidants such as vitamin E, which according to epidemiological data may have a powerful preventive effect, are currently caught in scientific limbo.

Antioxidants encompass a wide array of compounds in fruits, vegetables, and plant-derived beverages such as wine and tea, and many people already take antioxidant vitamins for general disease prevention. These chemicals can inhibit oxidative reactions that cause various types of tissue damage, including brain-cell injuries associated with Alzheimer’s disease.

But in several trials in which physicians have treated people with vitamin E in addition to approved Alzheimer’s drugs, the results have been inconsistent.

John C.S. Breitner of the University of Washington School of Medicine in Seattle and his colleagues reported in the January Archives of Neurology that among 4,740 apparently healthy people, those who regularly took pills containing vitamins E and C were just 36 percent as likely to develop Alzheimer’s within 3 years of joining the study as were people not taking the antioxidants. Neither vitamin alone had the effect. The findings come from an ongoing study started in 1995 of men and women living in Cache County, Utah.

Recent animal studies designed to shed light on whether vitamin E and other antioxidants work have been contradictory. In one encouraging study, for example, Cotman and his colleagues added vitamins E and C and some other antioxidants to the diet of aging beagles that showed some signs of cognitive impairment. While dogs on a normal diet continued to decline, dogs that ate the special chow each day gradually improved in their performance on an object-recognition test.

“That really startled us,” says Cotman, who discussed the findings in Seattle this February at a meeting of the American Association for the Advancement of Science. “They rejuvenated an aspect of brain function that they had when they were young but lost with age.”

Some animals had already developed beta-amyloid deposits before entering the experiment. Those plaques thickened and spread in dogs eating regular chow, but not in dogs on the special diet. “We basically froze the amyloid deposits in time with this diet,” Cotman says.

Other animal research suggests that dietary antioxidants are likely to change the course of Alzheimer’s only if they’re given early on. For example, when fed supplements of vitamin E beginning at age 5 months, mice genetically prone to build up beta-amyloid deposits in their brains develop about half as much of the substance as is typical of mice of that strain.

But the mice derive no benefit when they receive the antioxidant at 14 months of age, after plaque formation is well under way, according to Domenico Praticò of the University of Pennsylvania and his colleagues, who reported these findings in the February FASEB Journal.

“Once the plaque is deposited, there’s very little that an antioxidant can do,” suggests Praticò.

Harnessing hormones

Other promising treatments for Alzheimer’s have fizzled in treatment trials but may harbor potential in prevention. Past studies suggested, for instance, that women lowered their Alzheimer’s risk if they took supplements of the female sex hormone estrogen. The hormone may disrupt beta-amyloid plaques, fight inflammation, and combat certain other chemical stresses that can damage neurons.

But the encouraging findings contrast with worrisome data from hormone-replacement trials, notes Susan M. Resnick of the National Institute on Aging in Bethesda, Md.

Many women have taken estrogen, often in combination with the hormone progestin, to ease symptoms of menopause or to boost long-term health. The latter use is now discouraged because some large-scale studies showed that risks outweigh benefits.

For example, results from the Women’s Health Initiative Memory Study, or WHIMS, indicated that some 2,000 women past age 65 who received a combination of estrogen and progestin doubled, rather than reduced, their risk of dementia (SN: 5/31/03, p. 341: Available to subscribers at Flawed Therapy: Hormone replacement takes more hits).

A clue to reconciling the findings may lie in the ages at which women took hormones, Resnick says. Many women in the studies before WHIMS took estrogen during or shortly after menopause to ease symptoms of that transition. In contrast, doctors working on WHIMS prescribed supplemental estrogen to older women to test the hormone’s effects on several aspects of health.

The protective effect of hormone supplements on Alzheimer’s may disappear in life’s later years, Breitner suggests. In fact, preliminary data on several thousand postmenopausal women in Cache County support the notion that only relatively early use of hormones prevents Alzheimer’s. Volunteers who started hormone therapy well before entering the study appear to have less than a third of the risk of Alzheimer’s as compared with women who never received hormone-replacement therapy.

In contrast, women who started hormone therapy shortly before joining the study gained no benefit, Breitner and his colleagues reported in 2002. In fact, these women had more than twice the risk of developing Alzheimer’s as did women who hadn’t received hormones. That’s consistent with data from WHIMS, Breitner points out.

He estimates that the benefits of estrogen as a dementia preventive peter out about a decade before Alzheimer’s is detectable, and hormone therapy thereafter increases the risk. “What is protective earlier in life may become a risk factor as the disease process, still silent but ongoing, progresses [toward] dementia,” Breitner says.

Nonsteroidal anti-inflammatory drugs, or NSAIDs, offer a parallel case study. In the early 1990s, epidemiologists noticed that people who for various reasons had for several years regularly used these common medications—which include aspirin, ibuprofen, naproxen, and similar drugs—were about half as likely as nonusers to develop Alzheimer’s.

However, when doctors gave NSAIDs to people with mild or moderate Alzheimer’s, benefits were elusive. Two major trials published in the past year found no evidence that the drugs slow, let alone stop, progression of the disease.

In one of the studies, scientists at Merck Research Laboratories in Blue Bell, Pa., gave a daily pill of the drug rofecoxib (Vioxx), a Merck-patented NSAID prescribed for arthritis, or an inert pill to 692 people over age 50 who had early Alzheimer’s disease. The groups showed no difference in mental decline during the yearlong study, Christopher Lines and his colleagues reported in the Jan. 13 Neurology.

The finding echoed that reported by Paul S. Aisen of Georgetown University Medical Center in Washington, D.C., and his colleagues in the June 4, 2003 Journal of the American Medical Association. After studying volunteers with mild-to-moderate symptoms of Alzheimer’s disease for a year, the researchers determined that neither daily rofecoxib nor twice-daily naproxen (Aleve) produced significant benefits over an inert pill.

“This is a disease that probably unfolds over a period of many years,” says Breitner. “By the time people have mild cognitive impairment, it may be too late.

You’ve got tremendous destruction of [areas of] the brain that these drugs have no capacity to alter.”

NSAIDs may nevertheless protect brain cells during the extended run-up to Alzheimer’s, Breitner says. Calculations based on his data suggest that the opportunity for prevention ends about 2 years before onset of full-blown Alzheimer’s symptoms, he says.

Working with other researchers, Breitner recently embarked on a trial of NSAIDs as preventive medicine. So far, more than 2,200 people who have relatives with Alzheimer’s have enrolled, but the study will probably need to run 7 to 10 years before its data can show whether the drugs prevent the disease.

Says Breitner: “These kinds of [extended] trials are the only way that we can know whether these drugs really do what people think they do.”

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