Alzheimer's discovered early
Published: Sunday, January 6, 2008 at 6:01 a.m.
Last Modified: Sunday, January 6, 2008 at 12:00 a.m.
For a perfectly healthy woman, Dianne Kerley has had quite a few medical tests in recent years: MRI and PET scans of her brain, two spinal taps and hours of memory and thinking tests.
Kerley, 52, has spent much of her life in the shadow of an illness that gradually destroys memory, personality and the ability to think, speak, and live independently. Her mother, grandmother and a maternal great-aunt all developed Alzheimer's disease. Her mother, 78, is in a nursing home in the advanced stages of dementia, helpless and barely responsive.
Kerley is part of an ambitious new scientific effort to find ways to detect Alzheimer's disease at the earliest possible moment. Although the disease may seem like a calamity that strikes suddenly in old age, scientists now think it begins long before the mind fails.
"Alzheimer's disease may be a chronic condition in which changes begin in midlife or even earlier," said Dr. John C. Morris, director of the Alzheimer's Disease Research Center at Washington University in St. Louis, where Kerley volunteers for studies.
Currently, the diagnosis is not made until symptoms develop, and by then it may already be too late to rescue the brain. Drugs now in use temporarily ease symptoms for some, but cannot halt the underlying disease.
Many scientists believe the best hope of progress, maybe the only hope, lies in detecting the disease early and devising treatments to stop it before brain damage becomes extensive. Better still, they would like to intervene even sooner, by identifying risk factors and treating people preventively - the same strategy that has markedly lowered death rates from heart disease, stroke and some cancers.
So far, Alzheimer's has been unyielding. But research now under way may start answering major questions about when the disease begins and how best to fight it.
A radioactive dye called PIB (for Pittsburgh Compound B) has made it possible to use PET scans to find deposits of amyloid, an Alzheimer's-related protein, in the brains of live human beings. It may lead to earlier diagnosis, help doctors distinguish Alzheimer's from other forms of dementia and let them monitor the effects of treatment. Studies with the dye have already found significant deposits in 20 to 25 percent of seemingly normal people over 65, suggesting that they may be on the way to Alzheimer's, though only time will tell.
"PIB is about the future of where Alzheimer's disease needs to be," said Dr. William E. Klunk, a co-discoverer of the dye at the Alzheimer's research center at the University of Pittsburgh. "PIB is being used today to help determine whether drugs that are meant to prevent or remove amyloid from the brain are working, so we can find drugs that prevent the underlying pathology of the disease."
Currently, for the most common form of Alzheimer's disease, which occurs after age 65, there is no proven means of early detection, no definitive genetic test. But PIB tests might be ready before new treatments emerge, making it possible to predict who will develop Alzheimer's.
Researchers are also using MRI scans to look for early brain changes, and testing blood and spinal fluid for amyloid and other "biomarkers" to see if they can be used to predict Alzheimer's or find it early.
Studies of families in which multiple members have dementia are helping to sort out the genetic underpinnings of the disease.
Finally, experiments are under way to find out whether drugs and vaccines can remove amyloid from the brain or prevent its buildup, and whether doing so would help patients. The new drugs, unlike the ones currently available, have the potential to stop or slow the progress of the disease. At the very least, the drug studies will be the first real test of the leading theory of Alzheimer's, which blames amyloid for setting off a chain of events that ultimately ruin the brain.
Alzheimer's was first recognized 100 years ago, and in all that time science has been completely unable to change the course of the disease. Desperate families spend more than $1 billion a year on drugs approved for Alzheimer's that generally have only small effects, if any, on symptoms.
Alzheimer's is the most common cause of dementia. Five million people in the United States have Alzheimer's, most of them over 65. It is the nation's sixth leading cause of death by disease, killing nearly 66,000 people a year and probably contributing to many more deaths. By 2050, according to the Alzheimer's Association, 11 million to 16 million Americans will have the disease.
"Sixteen million is a future we can't countenance," said William H. Thies, the association's vice president for medical and scientific relations. "It will bankrupt our health care system."
The costs are already enormous, $148 billion a year - more than three times the cost of chronic lung disease, even though Alzheimer's kills only half as many people.
To a great extent, increases in dementia are the price of progress: More and more people are living long enough to get Alzheimer's, some because they survived heart disease, strokes or cancer. It is a cruel trade-off. The disease is by no means inevitable, but among people 85 and older, about 40 percent develop Alzheimer's and spend their so-called golden years in a thicket of confusion.
The potential market for prevention and treatment is enormous, and drug companies are eager to exploit it. If a drug could prevent Alzheimer's or just reduce the risk, as statins like Lipitor do for heart disease, half the population over 55 would probably need to take it, Thies said.
If new drugs do emerge, they will come from studies in patients who already have symptoms, Thies said. But he said the emphasis would quickly shift to treating people at risk, before symptoms set in.
Researchers are especially eager to study people like Kerley, because the children of Alzheimer's patients have a higher-than-average risk of dementia themselves, and tracking their brains and minds may open a window onto the earliest stages of the disease.
Some forgetfulness is normal. Distraction, stress, fatigue and medications can contribute. A joking rule of thumb about Alzheimer's is actually close to the truth: It's OK to forget where you put your keys, as long as you remember what a key is for.
Doctors use standard memory and reasoning tests to diagnose dementia, along with symptoms reported by the patient and family members. The term "mild cognitive impairment" is sometimes applied to small but measurable memory problems. But its meaning is unclear: Some studies find that the impairment can resolve itself, while others suggest it always progresses to dementia.
Even if older patients think more slowly or take longer to remember, as long as they can still function independently, they are not demented, Morris said.
Kerley suspects her mother's Alzheimer's disease began long before the official diagnosis in 2001 or even the tentative one in 1995 - years before, maybe decades. She wonders if the disease might explain, at least in part, her mother's difficult personality and lack of interest in reading or education.
When does Alzheimer's begin? The question haunts families and captivates scientists.
Morris said, "We think that by the time an individual begins to experience memory loss, there is already substantial brain damage in areas critical to memory and learning."
No one knows whether the disease affects thinking, mood or personality before memory fails. Researchers think the brain, like other vital organs, has a huge reserve capacity that can, at least for a time, hide the fact that a disease is steadily destroying it.
The disease is named for Alois Alzheimer, a German doctor who first described it in Auguste D., a 51-year-old patient he saw in 1901. Her memory, speech and comprehension were failing, and she suffered from hallucinations and paranoid delusions. Unable to finish writing her own name, she told Alzheimer, "I have lost myself."
She died in 1906, "completely apathetic," curled up in a fetal position and suffering from bedsores, Alzheimer wrote.
When Alzheimer dissected Auguste's brain, he found it markedly shrunken, a wasteland of dead and dying nerve cells littered with strange deposits.
There were two types of deposits, plaques and tangles. Plaques occur between nerve cells, and are now known to consist of clumps of beta amyloid, an abnormal protein. Tangles form inside nerve cells, and are made of a protein called tau that is normally part of a system of tubules that carry nutrients to feed the cell. Once tau is damaged, the nerve cells essentially starve to death.
Until the 1970s, Alzheimer's disease was considered a rare brain disorder that mysteriously struck younger people like Auguste D. It was thought to be different from "senility," which was assumed to be a consequence of aging. But then researchers compared the brains of younger people who had died of Alzheimer's with those of elderly people who had been senile, and discovered the same pathology - plaques and tangles. Senility, they decided, was not a natural part of aging; it was a disease.
The leading theory of Alzheimer's says that beta amyloid, or A-beta, is the main culprit, building gradually in the brain over decades and short-circuiting synapses, the junctions where nerve cells transmit signals to one other. Gradually, the theory goes, the cells quit working and die.
Everybody produces A-beta, but its purpose is not known. People who develop Alzheimer's either make too much or cannot get rid of it. People with the most common type of Alzheimer's, late-onset, probably have trouble clearing A-beta, researchers say. There are also forms of Alzheimer's that start early in life and are caused by rare genetic mutations; those patients probably produce too much A-beta.
Dr. Dennis J. Selkoe, a professor of neurologic diseases at Harvard, said that just as lowering cholesterol can prevent heart disease, lowering A-beta may prevent Alzheimer's or slow it, particularly in the early stages - provided that drugs can be created to do the job.
Several drugs and vaccines are now being tested that either block the production of A-beta or help the body get rid of it. Researchers are also testing anti-amyloid antibodies, which are proteins made by the immune system, as well as blood serum that contains the antibodies.
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