In the 10 years since Ronald Reagan hand-penned his poignant letter to the American people disclosing his diagnosis of Alzheimer's disease, great scientific progress has been made in understanding the nature of the affliction, but few of the findings have made their way into clinical practice.
Five drugs are now available in the United States that provide some relief of symptoms — and dozens more are under study. An experimental vaccine against Alzheimer's proved toxic in humans, but researchers are studying an improved version.
Small preliminary studies hint that gene therapy or implants of new brain cells may slow the course of the disease, but such approaches are years away from wide use.
Stem cell research, in particular, has been slow because of controversies surrounding the use of stem cells taken from human embryos. In May, Nancy Reagan made a plea for an acceleration in such research, saying that it could lead to a cure for people like her husband.
Federal research funding devoted to Alzheimer's has jumped from $298 million in 1994 to more than $650 million in the current fiscal year. The Alzheimer's Assn. has been lobbying for a $40-million increase in this year's funding and has a goal of $1 billion per year for the disease.
But it is still a race against time.
"There have been great increases in the amount of information, and it's an accelerating process," says Bill Thies, vice president for medical and scientific affairs for the Alzheimer's Assn.. "We are moving in the right direction, but it's clear that we aren't finished yet."
What worries experts the most is the explosion of cases that will almost certainly occur in the coming years with the aging of the baby boom population. Without a cure or more effective treatment — the therapies available provide only moderate symptomatic relief, with no effect on the causes — Alzheimer's will burgeon into a major public health problem.
Alzheimer's is a brain disorder that gradually destroys a person's memory. The number of people developing this affliction is expected to more than triple from the current 4.5 million to 16 million by the year 2050 — when every baby boomer will have turned 85.
Researchers are probing the mysteries of Alzheimer's on many fronts. Among them:
Brain cell regeneration: Most scientists believed that once a brain nerve cell died, it could not be replaced, and its function was lost forever. Their thinking has since changed, the result of studies in mice and monkeys that have shown cell regeneration, leading them to feel more optimistic about new cell growth, and the possibility of applying this knowledge to Alzheimer's disease.
One potential approach focuses on a substance in the brain called nerve growth factor. Scientists aren't yet sure exactly how nerve growth factor works; however, it is known to be one of several such neurotrophic factors in the brain. Although nerve cells in the brain cannot divide, they can repair themselves after injury, and neurotrophic factors promote this regeneration.
Researchers at UC San Diego in April reported results from an eight-patient study that suggested gene therapy increasing the concentration of nerve growth factor in the brain could slow the progression of the disease. They took skin cells from the patients, inserted the gene for nerve growth factor, then implanted the cells into brain regions affected by Alzheimer's. Although the purpose of the study was to determine the safety of the procedure, Dr. Mark H. Tuszynski and his colleagues found that deterioration of the patient's faculties slowed after the procedure.
Diagnosis: There is no laboratory test that can diagnose Alzheimer's. But researchers such as Dr. Gary W. Small, director of the UCLA Center on Aging, have shown that positron emission tomography, or PET, scanning can accurately detect Alzheimer's in its early stages.
Drugs: This is regarded as a crucial area of exploration. Five drugs have been approved by the Food and Drug Administration for the treatment of Alzheimer's disease: tacrine (Cognex); donepezil (Aricept); rivastigmine (Exelon); galantamine (Reminyl); and memantine (Namenda). Tacrine was the first to be approved but is rarely used anymore because of the possibility of serious side effects, including liver damage.
Tacrine, donepezil, rivastigmine and galantamine belong to a class of drugs called cholinesterase inhibitors. Each acts in a different way to block the breakdown of acetylcholine, a brain chemical that is important for memory. Memantine shields the brain from overexposure to another neurochemical called glutamate. High levels of glutamate associated with Alzheimer's kill brain cells.
Each of the drugs provide limited benefits to select groups of patients, but none provides dramatic results in delaying the course of the disease. All cost about $120 per month, and more than 1 million Americans are taking them regularly.
At least two dozen other potential drugs are being studied, but there is no evidence so far that any will provide a major breakthrough.
Strong evidence suggests that vitamin E in relatively high doses may slow disease progression in some patients. Some evidence suggests that the Parkinson's drug selegiline (Carbex or Eldepryl) may also improve thought processes.
Some studies also suggest that prednisone and a group of drugs called nonsteroidal anti-inflammatory drugs — such as aspirin and ibuprofen — may benefit patients by limiting the inflammation associated with Alzheimer's.
Some research had also suggested that estrogen could benefit female Alzheimer's patients, but a major clinical trial showed that it was of no value.
Studies in mice had indicated that an experimental vaccine developed by Elan Corp. could remove the brain plaques thought to cause Alzheimer's, but human trials were halted in 2002 when the vaccine was found to provoke inflammation in the brains of 6% of the patients. Elan is now studying an improved version that researchers hope will overcome this problem.
Genes: Currently, at least four genes can be linked to Alzheimer's. Although researchers know a considerable amount about the genetics of Alzheimer's, they suspect that other genes also play a role in the development of the disease.
Stem cells: In the long run, researchers hold the greatest hope for the use of stem cells to replace lost brain cells.
Stem cells are primitive cells, usually derived from embryonic tissue, that have the potential to become any type of body cell. Injected into the brain, the stem cells would become brain cells themselves, replacing those lost to disease and restoring function — or at least delaying further deterioration.
Nancy Reagan's embrace of stem cell research comes as a challenge to President Bush.
By executive order, he has limited the use of federal funds to researching a small number of cell colonies already extracted from embryos, to avoid doing anything that would "encourage further destruction of human embryos."
In an implicit referendum on Bush's order, a California initiative qualified last week for the November ballot that would have state taxpayers underwrite $3 billion worth of stem cell research.
Advocates said it could lead to breakthroughs in curing Alzheimer's, as well as numerous other diseases.
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'Able to raise public awareness'
Text of the letter written by Ronald Reagan in November 1994 announcing that he had Alzheimer's disease:
My Fellow Americans,
I have recently been told that I am one of the millions of Americans who will be afflicted with Alzheimer's disease.
Upon learning this news, Nancy and I had to decide whether as private citizens we would keep this a private matter or whether we would make this news known in a public way.
In the past, Nancy suffered from breast cancer, and I had my cancer surgeries. We found through our open disclosures we were able to raise public awareness. We were happy that as a result many more people underwent testing.
They were treated in early stages and able to return to normal, healthy lives.
So now, we feel it is important to share it with you. In opening our hearts, we hope this might promote greater awareness of this condition. Perhaps it will encourage a clearer understanding of the individuals and families who are affected by it.
At the moment, I feel just fine. I intend to live the remainder of the years God gives me on this earth doing the things I have always done. I will continue to share life's journey with my beloved Nancy and my family. I plan to enjoy the great outdoors and stay in touch with my friends and supporters.
Unfortunately, as Alzheimer's disease progresses, the family often bears a heavy burden. I only wish there was some way I could spare Nancy from this painful experience. When the time comes, I am confident that with your help she will face it with faith and courage.
In closing let me thank you, the American people, for giving me the great honor of allowing me to serve as your president. When the Lord calls me home, whenever that may be, I will leave with the greatest love for this country of ours and eternal optimism for its future.
I now begin the journey that will lead me into the sunset of my life. I know that for America there will always be a bright dawn ahead.
Thank you, my friends. May God always bless you.