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Researchers race to beat scourge of aging

Sunday, December 10, 2000

By Gary Rotstein, Post-Gazette Staff Writer

Untangling Alzheimer's
Part One of three

It took nine decades from the discovery of Alzheimer's disease to develop the first weapons to fight it -- drugs that can slow but not stop its mind-crippling symptoms.

Dr. Steven DeKosky, director of the University of Pittsburgh's Alzheimer Disease Research Center, is a leading national authority on the disease. He runs weekly meetings that assess the condition on the center's patients, using tools such as the magnetic resonance imaging of the brain activity is shown in the background. (Andy Starnes, Post-Gazette)

Now, research on the late-life scourge has accelerated so dramatically that many believe the next decade will yield the keys that the 20th century couldn't -- to either cure, prevent or effectively treat this leading cause of dementia.

No one's promising relief for the several million Americans and their caregivers already bedeviled by the uncertainty, confusion and ultimate mental chaos of Alzheimer's. It may be those stricken after them who will benefit from new research, but even that represents a remarkable turnaround from a mindset that until the last quarter century considered senility a sign of normal aging, with nothing to be done about a person's gradual loss of recall and reasoning.

The hope is that before baby boomers start turning 65 in 2011, vastly enlarging the potential ranks of those with Alzheimer's, the disease will be diminished if not conquered. Dr. Donald Price, a Johns Hopkins Medical Institution neuropathologist, is among many research leaders who believe the field is on the threshold of breakthroughs.

"Ten years ago, if you had told me we would have this kind of progress in Alzheimer's disease, I would have thought you were wrong," Price said. "I don't think anyone anticipates this kind of progress for a major disease of this type so quickly."

Such optimism contrasts with a disease that has been notorious for its unforgiving bleakness, even compared to other deadly illnesses such as stroke and cancer. Those can be treated and defeated, or at least contained, for a healthy percentage of patients.

Alzheimer's, by far the most common type of dementia, has instead been an unrelenting malady. The mind wanders down a progressive slope, from initial forgetfulness to a point where nothing and no one in the world seems familiar. Caregivers end up with the strain of handling all of the basic tasks for a loved one who can't even recognize them, let alone return the love.

This loss of self-awareness leaves an Alzheimer's patient such as former President Ronald Reagan no more clued in to his role in the world than someone from the most menial background -- a stealthy equalizer that erases the essence of its victims more so than the many physical afflictions of old age.

"It comes on sort of slowly, so it's not always so obvious, but there is this kind of sense of loss of self that I think is a real scary thing for people, and it's scary for the caregivers, too," observed Dr. T. Franklin Williams, a geriatrician who headed the National Institute on Aging from 1983-91. "You're really losing who you are, and that's a devastating thing to try to deal with."

Untangling Alzheimer's
Part One of three

Pitt doctor lends voice, research to the fight

Graphic: U.S. Alzheimer's disease projections

Part Two:
Alzheimer's patients follow different paths to a final debilitation

Part Three:
Burden of illness often heaviest for caregivers

Staff biographies

Staff writer Gary Rotstein, 42, us a member of the Post-Gazette's issues team and specializes in aging issues. He has held a variety of writing and editing positions with the news paper since 1983. His most recent series examined trends in the funeral industry and how Pittsburgh's large elderly population has shaped the region.

Staff photographer Andy Starnes, 50, splits his time at the Post-Gazette between photography and photo editing. He joined the paper in 1993 and previously worked for the Pittsburgh Press. His latest projects focused on the funeral industry and on how a little boy and his family coped with serious illness. Starnes holds a degree in psychology and lives in Regent Square.


A race against time

Academic researchers and pharmaceutical companies across the country see their race against Alzheimer's through the prism of unprecedented demographic shifts.

The facts are simple: The likelihood of getting Alzheimer's is closely tied to age, and America is aging quickly. The 85-and-over population is the fastest-growing group in America -- expected to double over the next 30 years and quadruple by 2050.

Alzheimer's and other dementias may afflict about 10 percent of the population over age 65, but studies suggest the rate is nearly 50 percent for those 85 and over. Once past age 65, the odds of getting Alzheimer's double every five years. A younger version of the disease, called "early onset," affects people in middle age and represents less than 10 percent of cases.

The Alzheimer's Association estimates that, based on Allegheny County's relatively old population, nearly 30,000 of its residents have the disease and another 20,000 have other forms of dementia.

Alzheimer's typically lasts eight to 12 years from the first evidence of pronounced, short-term memory loss until death, which often is triggered by pneumonia, infection or nutritional deficiencies arising as people can no longer take care of themselves or follow instructions.

The effects leave Mary Gonzales, 86, of Elizabeth Township, following grandson Donald Helton around the home they share, talking about her dead daughters as though they're still alive, addressing the faces she sees in pictures as though they're real.

"She doesn't know where she's at any more, and it's like taking care of a baby," Helton, 29, explains about his physically fit grandmother. He is determined, however, to continue caring for her at home, where she seems contented, instead of placing her in an institution.

Former schoolteacher Diane Eisen, 63, is in an earlier but clearly declining stage of the disease. She's more aware of her surroundings than Gonzales but unable to help her husband care for the retarded, adult son who lives with them in their Mt. Lebanon home. She can't drive, can't shop, can't cook, and looks down sadly while telling others at a support group of the local Alzheimer's Association: "I'm an extra."

And the effects frustrate Irene Vellella, 77, even though she's in the mildest stage where she's still able to live alone and function independently in a Bellevue apartment. She has trouble recalling details of her past that would have rolled off her tongue a few years ago, and like other sufferers, she can't always think of the words she wants to say.

"I hate this -- it makes me feel stupid," she fumes. "I just got this thing -- I can't tell -- this thing just starting like this."

The national Alzheimer's Association estimates 4 million Americans have some form of dementia, with the number potentially growing to 14 million by 2050 if the disease is not reduced or stopped in the meantime. The accuracy of those numbers is sometimes debated, because Alzheimer's and other forms of dementia defy easy diagnosis, but no one questions that the prevalence is likely to soar.

"The number of people with Alzheimer's in the United States is increasing as we speak, has been increasing for a number of years, and will be for the foreseeable future," said Dr. Denis Evans, director of the Rush Center for Healthy Aging in Chicago, whose epidemiological work in 1989 was the basis for many assumptions about Alzheimer's prevalence.

Irene Vellella of Bellevue, who is in the early stages of Alzheimer's, is still able to function independently but unable to remember things she once did. "I hate this - it makes me feel stupid," she says. (Andy Starnes, Post-Gazette)

Raising awareness

The growth of the elderly population is no sudden surprise, and the government's focus on seniors' health issues in the 1970s helped create the impetus to deal with Alzheimer's today. Leaders of the National Institute on Aging made the disease their top priority after its formation in 1974 because it received so little attention compared to other late-life ailments.

A small group of advocates tried to raise public awareness by forming the national Alzheimer's Association in 1980. The group didn't stay small for long. A woman who signed her letter "Desperate" wrote that year to the nationally syndicated advice column, Dear Abby, wanting to know if anyone could help her deal with her husband's disease. When Abby publicized the new association's address, 25,000 letters flooded its one-person office within days.

In 1984, the National Institute on Aging began establishing Alzheimer's disease centers around the country to propel better scientific understanding of the disease, with the University of Pittsburgh's among the first 10 of them. Federal funding of Alzheimer's research has since grown to $466 million annually, more than three times what it was a decade ago.

Findings from those centers and elsewhere about the possible causes of Alzheimer's and how it develops inside the brain led to a rush within the pharmaceutical industry in the 1990s to try to cure the disease. It's an achievement that would be worth vast sums for whichever company can stake a claim.

Looking under his microscope 94 years ago at brain tissue of a deceased German woman who'd suffered from dementia, Dr. Alois Alzheimer identified the two disruptive hallmarks that researchers have most associated with the disease ever since.

One is the amyloid plaque that clouds the area between the nerve cells, or neurons, of the brain. These are sticky clumps of protein that researchers believe interfere with memory and other cognitive functions. While plaque also arises in the brain as part of normal aging, greater quantities exist in people who exhibited memory problems before death, and still larger amounts occur in people who were severe Alzheimer's patients.

The other feature long identified with Alzheimer's are abnormal tangles that build up directly inside the brain's nerve cells. These twisted threads of a protein called tau are suspected of interfering with the essential communication between neurons and could cause the death of nerve cells.

While researchers know the plaques and tangles exist in Alzheimer's patients in a way that differs from people who age normally, they've never really determined which feature may be more important and whether those actually provoke the disease's symptoms or are just a by-product of some other cause.

Still, the presumption has been that eradicating or preventing the plaques and tangles will keep an otherwise healthy person's mind free of serious defects. Occasional short-term memory lapses -- like forgetting a name or where you've placed keys -- are considered normal in aging.

For many years, professionals studied the disease and those plagued by it while unable to do much for them. Neurologists referred to such cases as a matter of "diagnose and adios," with little to gain by investing large amounts of time with patients.

That changed in 1993 when the first drug developed specifically for Alzheimer's won governmental approval. By inhibiting an enzyme that disrupted cognitive functioning, the drug -- Cognex -- brought a concrete pharmaceutical focus to a disease whose symptoms had been treated only generally with anti-depressants and anti-anxiety medications.

Cognex is no longer used much because of potentially harmful side effects, but two more Alzheimer's drugs have been developed since to serve the same purpose more safely: Aricept, which is the most commonly used, and Exelon, approved by the Food and Drug Administration earlier this year. Another drug, Reminyl, is expected to be approved and marketed next year. Individuals respond differently to each of the drugs, and it's unclear as yet if any one of them is the most effective.

The best-case scenario described by most Alzheimer's clinicians for the drugs is that they slow down the disease for perhaps a year or more. They don't cure a person and don't necessarily recover any lost mental abilities, but they can stabilize the condition so people have a longer period of functioning close to normal.

Dr. William Klunk, director of psychiatry for the Pittsburgh Alzheimer Disease Research Center, tells patients that current drugs slow the disease in about half the people who use them. The cost of the prescription pills is typically $100 to $150 a month.

"It's kind of dismal compared to other diseases. ... We're going up against a gun ship with a squirt gun," Klunk said of the current medications, despite the moderate help patients may get.

Diane Eisen of Mt. Lebanon is one of an estimate 4 million Americans with Alzheimer's or other forms of dementia. She feels like "an extra" in her own home because she's unable to help her husband with any tasks, including care of their retarded son. (Andy Starnes, Post-Gazette)

A boom in research

Despair felt by many doctors and families dealing with the disease currently can be juxtaposed with the volume of research taking place on Alzheimer's. The number of articles published on the disease in medical and scientific journals grew from 294 in the 1970s to 5,233 in the 1980s to 15,905 in the 1990s.

In multiple studies with different wrinkles across the nation, researchers are examining the effects of vitamin E, estrogen, ginkgo biloba and anti-inflammatory medications such as ibuprofen and its more potent cousins. Various studies have suggested that some of those could help prevent the disease though varied results have prevented any official pronouncements.

Simultaneously, others are trying to identify more genes linked to Alzheimer's, in order to better predict who will get it. The rare early-onset version of the disease is one that is inherited from parents -- with a 50-50 chance that a disease-causing gene will be passed on to a child -- but there's less known about the genetics of the more common late-life Alzheimer's. One identified gene increases the risk for someone carrying it, but it doesn't necessarily result in the disease.

Still other researchers are focused on advancing the state of neuroimaging to where a patient's response to treatment can be closely monitored through magnetic resonance imaging or a positron emission tomography scan, which analyzes the brain's activity level as it functions.

Now, the only confirmed diagnosis can be made in a brain autopsy after death. A small group gathers in the University of Pittsburgh's Scaife Hall for this purpose each Tuesday morning under the tutelage of Dr. Ronald Hamilton. The neuropathologist in minutes can nimbly reduce a donated 2-pound brain to dozens of thumb-size slices for microscopic examination, helping determine if the deceased's memory loss and wandering tendencies were really Alzheimer's.

"You can have a lot of these changes and not be sure that there's Alzheimer's disease," Hamilton explained.

A diagnosis of probable Alzheimer's prior to autopsy can be made by knowledgeable clinicians in about 90 percent of cases, with imaging techniques able to assist in that, but researchers expect one day that the MRI and PET scans will accurately anticipate and diagnose the disease in living patients.

Dr. Steven DeKosky, director of Pitt's Alzheimer Disease Research Center, says the goal for many researchers is to find a way to delay the disease for at least a few years, which would allow many people's minds to stay healthy until they succumb to some other physical disease.

"We don't have to keep it at bay all that long, because the majority of people get it at 75 or 80," said DeKosky, a neurologist who is heading a major national study of ginkgo biloba that is just under way.

Such work has expanded beyond just Alzheimer's patients to assess people with a less severe form of memory loss, called mild cognitive impairment, and even those who are aging but still normal. The idea is to see if any of the potential treatments reduces the rate at which people develop Alzheimer's. Healthy older adults have about a 1 to 2 percent chance each year of getting the disease, and those with mild cognitive impairment develop it at a rate of 12 to 15 percent.

"Many people are turning their interest toward milder and milder aspects of the disease, with the idea to determine if we can prevent it rather than treat it. Later on, the neurologic damage may be too great to reverse it," said Dr. Ronald Petersen of the Mayo Clinic, who is heading a national study of the effects of Aricept and vitamin E when administered early on to people with mild cognitive impairment.

Attacking at the source

The greatest long-term prospect for the field comes from the possibility of wiping out or preventing buildup of amyloid plaque, which no existing drugs do. Scientists are further along in understanding the plaques than tangles, and banking on the idea that if they can address the plaque, they can address the disease.

Elan Corp. made headlines last year by announcing a possible vaccine, which had reduced plaque among mice that had been given a mutated gene to develop some of the pathology of Alzheimer's.

For the first time, someone had identified a potential method of undoing or preventing Alzheimer's, although experts were also cautious: The vaccine hadn't been tried in humans; there was no certainty that erasing plaque would improve cognition; and it had no known impact on tangles, which no one has figured out how to pair with plaque in laboratory animals.

Since then, independent researchers have duplicated the vaccine's success by removing plaque in mice, and they added to the finding by verifying that the animals' mental functioning improved afterward. Elan also has determined in preliminary trials that the vaccine shows no harmful side effects on humans, and it is preparing to start broader trials on Alzheimer's patients next year.

Because of the stringent Food and Drug Administration regulatory process, a drug starting clinical trials now is probably at least four years away from being marketed to the public, assuming it is proven effective. Alzheimer's experts, like Elan itself, are careful to temper optimism about the vaccine while holding out hope of its benefits.

"It's possible that you could eliminate amyloid lesions from the brain but have no effect on the clinical picture. It would be a scientific curiosity, but one that's not marketed," theorized Dr. Zaven Khachaturian, a consultant to industry who developed the government's initial Alzheimer's research program.

New findings, viewed with as much potential as the vaccine, focus on the possibility of blocking the buildup of amyloid plaque rather than attacking it later. Pharmaceutical companies and academic researchers have identified enzymes they believe help create the sticky protein, and they're hoping to limit the enzymes.

Bristol-Myers Squibb Co. has reported success in inhibiting the enzyme called gamma secretase in mice and stopping their development of plaque. It is now testing the safety of the drug on humans, hoping to receive FDA approval next year to test its effectiveness on early Alzheimer's patients.

Other companies are betting on a different enzyme, beta secretase, as the culprit to be attacked in plaque buildup. Their research isn't as far along, and just as with the vaccine, no one's sure yet whether either enzyme-inhibiting theory ultimately is effective in retaining mental functioning.

What is certain is that such efforts to address the underpinnings of Alzheimer's are more advanced than ever before, and "every year accelerates at a more rapid pace," said Dr. Marcelle Morrison-Bogorad, associate director of neuroscience and the neuropsychology of aging at the National Institute on Aging

"I think we will know in four or five years whether quite a large number of promising approaches to Alzheimer's work or don't work," she said.


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