Some researchers suspect no silver bullet exists to stop this complex disease, so research is being carried out in areas as diverse as drugs, vaccines and stem cells.
By SUSAN ASCHOFF
Published June 27, 2004
[Times photo: Ken Helle 2001]
A mouse at the Roskamp Institute noses around items from a toy bin in a test of its curiosity about unfamiliar objects.
[Getty Images]
Nancy Reagan says a final farewell to her husband, former President Ronald Reagan, who died of Alzheimer’s complications. The former first lady advocates stem cell research to combat the disease.
David Morgan, Ph.D
[Times photo: Ken Helle 2001]
A mouse at the Roskamp Institute peeks through a hole in a testing chamber, checking if it’s the hole that leads to the rodent’s secure hiding place. The facility uses mice in its Alzheimer’s research.
The former first lady has always had a bare-knuckled determination to take care of her man. So a month before Ronald Reagan's death from Alzheimer's disease, Nancy Reagan spoke publicly for the first time in favor of stem cell research, breaking ranks with many in her husband's political party, including President Bush.
Scientists want no avenue of research closed to them. But many believe the answers to the devastating brain disease will come from other directions.
More than 50 drugs are in the pipeline. And in laboratories from Tampa to Reagan's home state, California, work proceeds on potential vaccines, chemical blockers and clues provided by genetically altered mice.
Almost a dozen "mechanistically distinct approaches" are under way, says David Morgan, Ph.D., a professor of pharmacology at the University of South Florida College of Medicine.
"I don't think cell therapy is going to be (the first) treatment to slow progress of Alzheimer's disease," Morgan says, and others agree. "I think any of these others are going to be developed in the next five years."
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Alzheimer's disease compromises the brain's function as computer and chemical factory. Connections between cells are lost, neurons die, and a protein called amyloid builds up between cells while other protein tangles within them. The resultant mess is daunting, but its complexity provides multiple targets for intervention.
Researchers, uncertain about the cause of Alzheimer's, are seeking to eliminate its pathology or block the disease from beginning.
An experimental vaccine to prompt the body's defenses to attack amyloid plaques in the brain, the telltale sign of Alzheimer's disease, appeared to stabilize cognitive deterioration in some patients. But a key trial was halted in 2002 when several recipients suffered brain inflammation. Work continues in labs across the country.
USF's Morgan will soon begin a trial on immunotherapy, injecting antibodies rather than stimulating a patient's body to make its own, as a vaccine does. This method, called passive immunization, is thought to be safer and has succeeded in mice.
Other drugs designed to stop amyloid from clumping are in development at several drug companies. Amyloid is particularly sticky when combined with sugar or zinc, so some researchers are looking for ways to rid the brain of excesses.
A "smoking gun" for amyloid plaque, a protein called apolipoprotein, or apoE, is another target. But no one is certain how apoE's malfunction increases risk for the disease.
Roskamp Institute in Sarasota was one of the first labs to find the amyloid mutation that defines Alzheimer's. Now its director, Dr. Michael Mullan, worries that the focus on amyloid will deter research on other suspected culprits.
"Amyloid is being overproduced, but it may be because something is missing that knocks it out," he says. Eliminate amyloid plaque and medicine is still left with the tangled pathology within cells. There, the action of a protein called Tau, which helps support nerve cell structure, has gone haywire.
Mullan and others believe the answer may lie with enzymes. Amyloid forms when a brain protein called amyloid precursor protein breaks down abnormally through the actions of beta secretase and gamma secretase. Scientists have been searching almost a decade for a drug to alter the actions of these enzymes.
Others are tapping existing drugs for new duty.
Dr. Constantine Lyketsos at Johns Hopkins University is recruiting healthy people in their 70s and 80s to take anti-inflammatory drugs such as Celebrex and Aleve. If nerve cells in Alzheimer's patients are dying because of a faulty immune response, suppressing inflammation or infection could interrupt the process, he says.
Cholesterol-lowering drugs called statins, which reduce plaque in blood vessels, are also being examined as amyloid busters. A trial with Lipitor suggested a reduced risk for Alzheimer's. The National Institute on Aging is conducting a large trial with Zocor. One day a blood test may identify people with high levels of amyloid, much as such a test finds those with high cholesterol, for intervention to ward off Alzheimer's.
Scientists still do not know the primary villain in Alzheimer's disease.
Their challenge is to prove the effectiveness and safety for humans of treatments now relegated to petri dishes, rats and monkeys.
"What I teach to the medical students about Alzheimer's disease, essentially 90 percent of it was unknown 10 years ago," says Huntington Potter, interim CEO of the Johnnie B. Byrd Sr. Alzheimer's Center & Research Institute in Tampa.
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Alzheimer's typically strikes people in their 60s and 70s. One in 10 people over 65 will get Alzheimer's, and almost half of those 85 and older will be afflicted, says Gloria Smith, president of the Alzheimer's Association's Florida Gulf Coast Chapter.
Only eight states have more total cases than the 17-county Gulf Coast area, she says.
The national association budgeted almost $17-million this year for research.
"If we can delay (onset of Alzheimer's) for just five years, we can save $50-billion a year in medical care costs, enough to insure everyone in the country," USF's Morgan says.
"I hope the cure comes fast," says Carol Ross of Clearwater.
The realization that her mother was seriously ill came five years ago when police called to say the 81-year-old, confused and sobbing, was at a McDonald's. Ross' mother had been sitting in the restaurant all day. The police found Ross' name in her purse.
Soon Ross got a diagnosis: Alzheimer's disease. She knew little, she says, except that another family, the Reagans, had recently announced that they, too, were dealing with the disease's pain.
Ross' mother has benefited from one of a handful of new drugs that slow Alzheimer's progression. Lucy Kasheta takes Reminyl twice a day, and Ross says the medicine makes her mother more herself. Other drugs newly approved by the Food and Drug Administration are Cognex, Aricept, Exelon and Namenda.
This year Ross put her mom, who once supervised large department stores and avidly filled in the daily crossword puzzle, in an assisted living facility.
"She has turned into the little girl. That's what breaks my heart."
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One in 10 Alzheimer's patients has a genetic predisposition. The other nine, Johns Hopkins' Lyketsos says, may fall prey to the disease through three or four pathways, genetic and environmental.
So research runs the gamut, from futuristic work on implanting stem cells to administering megadoses of vitamins to people with mild Alzheimer's to lower levels of homocysteine, an amino acid associated with the disease. A vitamin trial will begin soon in Tampa, one of 30 sites nationwide.
"Alzheimer's is so complex. My hunch is that we need to develop stem cells for other diseases such as Parkinson's," Lyketsos says. Stem cells could one day repair a diabetic child's pancreas so he no longer needs insulin or regenerate heart muscle destroyed by a heart attack.
But stem cells are not the dutiful soldiers scientists would prefer.
Embryonic stem cells "are like babies with guns. It's very difficult to control them," the Roskamp Institute's Mullan says.
"We say, "These cells know what they're doing' " if we implant them in a human. "They don't."
The neurons dying from Alzheimer's are part of a person's memory circuit, he says, the "who and what we are." Implanting a new cell will not replace the one that remembers a spouse's name.
But a biology professor at the University of Central Florida is among the many who believe stem cells will be the ultimate answer to Alzheimer's destruction. Kiminobu Sugaya, Ph.D., transplants human neuro stem cells in rats' brains and reports dramatic memory improvement. He compared the rodents' performance before and after swimming across a pool of water to a submerged platform, guided by objects on a wall. This kind of spatial memory, Sugaya says, is particularly affected in Alzheimer's patients, who get lost driving home from the neighborhood grocery store.
Trials in humans are five or six years away, he says.
"I have done a lot of study of therapies that might reduce the progress of the disease, but the neuron will never come back," Sugaya says. "The final cure has to regenerate the neuron."
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Regeneration requires cells.
Stem cells have the ability to develop into the various kinds of cells that make up the tissues and organs of the body. Most become specialized, doing their designated job of making muscle or bone or brain. Doctors grow sheets of skin on scaffolding for burn victims using skin cells taken from the patient.
Skin cells, in this example, make skin cells.
But humans begin as undifferentiated stem cells, and these embryonic cells are uniquely suited to making repairs. They are pluripotent: Their potential use is unlimited. By adding nutrients and hormones, scientists coax them to perform desired functions, then transplant them to replace dead or defective cells.
Scientists obtain embryos, which would otherwise be discarded, from fertility clinics with parents' permission. An embryo is created when a sperm fertilizes an egg and the egg divides into two cells. After about five days, a hollow sphere called a blastocyst forms that contains stem cells for all the parts of the body.
Scientists also clone cells in the laboratory. Called somatic cell nuclear transfer, or SCNT, the cloned cells begin with an unfertilized egg whose nucleus is replaced with genetic material, then stimulated to divide.
Opponents of embryonic stem cell research urge scientists to instead use stem cells taken from adults.
But adult stem cells are partly specialized and difficult to locate. They are multipotent: They can develop into only certain types of cells. With great difficulty, scientists can manipulate them with chemicals or genes to develop other kinds of tissue. But this quality, called plasticity, has its limits. At the University of Florida and other labs, researchers report that adult stem cell adaptability may result from the accidental presence of pluripotent cells.
Any stem cell treatment for Alzheimer's disease is probably more than a decade away. Results in animal experiments have been mixed.
"It's important for the public to understand that we know nothing . . . unless we've tested it extensively," Morgan cautions.
In the infinite complexity of the human body, friends and foes are the same. At the Roskamp Institute, researchers this month announced their discovery that the amyloid beta peptide that causes Alzheimer's plaque also stops growth of cancer tumors in mice. And though researchers believe targeting the apoE protein could prevent plaque in the brain, outside the brain, apoE keeps cholesterol from clogging the bloodstream.
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Nancy Reagan wrote to Bush before the president's announcement on stem cell funding, urging him to support "a promising path to a cure."
In the first public survey on the issue since Ronald Reagan's death, almost two-thirds of Americans said they wanted the federal government to increase funding, reported Results for America, a nonprofit group addressing societal issues.
More than 200 members of Congress, many of them Republicans, sent letters to Bush in April and June asking him to ease restrictions.
And in California, a proposal to contribute $3-billion to stem cell research is on the November ballot after supporters gathered more than 1-million signatures.
Stem cells removed from the body cannot form another embryo or develop into a human. But Bush and many other Americans believe human life begins with a single fertilized egg.
Bush has rejected renewed calls to relax restrictions on stem cell research he ordered in August 2001. He believes his policy is the right one, White House spokesman Scott McClellan said on June 14. "It doesn't cross a certain moral threshold that he set," McClellan said.
Under Bush's executive order, federal funds pay for research on 78 embryonic stem cell lines, or colonies, in existence at the time. A stem cell line is made up of millions of cells grown in petri dishes from the approximately 30 cells in a 5-day-old embryo. Of those 78 lines, only 15 have proven viable for research, critics say. By contrast, an estimated 400,000 embyros are in fertilization clinics, and most of them will be destroyed.
"I'd be surprised," Lyketsos says, "if there is a scientist who doesn't see (limits on stem cell research) as a lost opportunity."
Alzheimer's patients die, on average, eight years after symptoms appear, though some may linger longer. Any treatment that stalls the disease's onset or moderates its symptoms can give families not only time, but the loved one they've lost.
"You have no idea how lonely it feels," says Edwin Kuester, whose wife of 65 years is in a nursing home, taken from him by Alzheimer's disease.
"She gives me a big smile when I visit her. She recognizes me," he says. "But I don't think she knows who I am."
