Jane Wirsig first started complaining of persistent fatigue in 1976, but the watershed event in the Princeton, N.J., woman's illness came while she was doing her household accounts the next year. She abruptly stood up, slapped her leg in frustration, and told her husband, Woodrow, "Something's wrong. I've forgotten how to subtract."
Wirsig was one of 4 million Americans who suffer from Alzheimer's disease. By 1986, she couldn't walk, couldn't talk, didn't recognize her husband and choked on her food.
That year, her husband enrolled her in an early experimental trial of a recently approved Alzheimer's drug called tacrine, and her condition immediately improved. "She stopped choking, she could walk again, and best of all . . . she could recognize me and tell me 'I love you, too,' " Woodrow Wirsig said. "The (drug) gave my wife another three years of an acceptable quality of life" before she died in 1989 at age 69.
Jane Wirsig's story, told in Woodrow's book, "I Love You, Too," is one that is likely to be repeated in the future.
In the last two years, researchers have been reporting unprecedented successes in understanding the causes of Alzheimer's disease and developing therapies.
Spurred by the recent discovery of genes that promise to provide an explanation of how Alzheimer's develops, some researchers believe that they are on the verge of producing revolutionary treatments to delay the onset of Alzheimer's disease, and perhaps prevent it.
"I am absolutely convinced that within 10 years we will have a pill that prevents Alzheimer's disease," said Dr. Allen Roses of Duke University, who discovered the genetic link.
Tacrine is still the only approved Alzheimer's drug, but two others, estrogen and an anti-inflammatory called indomethacin, have been shown in recent small studies to delay the onset of the disease and reduce its effects. At least 15 other drugs are in clinical trials. Grafts of fetal cells are also likely to be tried as therapy within the next six months.
Perhaps the greatest excitement revolves around the recent genetic discovery linking Alzheimer's to a protein that carries fats in the blood.
"These are exciting times. Much more has happened just in the last three years than has happened in the last three decades," said Dr. Leonard Berg of the Washington University School of Medicine, chairman of the medical and scientific advisory board of the Alzheimer's Assn. "I have the clear sense that scientists across the country are much more enthusiastic that we will come up with some better answers in the next few years than they were even five years ago."
"For the first time, I feel optimistic that (researchers will be able) to discover effective new drugs," said neuroscientist Richard Wurtman of the Massachusetts Institute of Technology.
The new findings are thought to be so important that researchers and the Alzheimer's Assn. are mobilizing an all-out effort to obtain $100 million in additional research funds from Congress to follow up on them. "It's time to redouble our efforts now that we are seeing a real payoff" in research results, said Joe Roth, association chairman.
Alzheimer's is a disease of aging. It affects perhaps 3% of people ages 65 to 74, 20% of those 74 to 84, and as many as 50% of those over 85. Moreover, the number of people over age 65, and thus at risk, is expected to double within the next 30 years, bringing a strong sense of urgency to the search for new therapies and preventives for Alzheimer's.
The disorder is characterized by a progressive loss of mental function, including loss of memory, language and the ability to deal with numbers. Victims progress further into confusion and a complete inability to handle normal everyday situations, failing to remember even their own names. When the brain finally loses the ability to regulate even elementary body functions, they die of malnutrition, dehydration, infection or heart failure.
The most distinguishing characteristic of the disorder is the presence of rock-hard plaques and tangles in the brain, which are used after death to make a definitive diagnosis of Alzheimer's.
The average time from diagnosis to death is usually seven to 10 years, but it can be as short as two or as long as 20. About 100,000 people die of Alzheimer's each year in the United States.
The effects of Alzheimer's can be devastating not only to the patients but to their families as well.
Barbara Stratford's father, J. Allen Stratford, developed the disorder in 1988 at age 66. An outgoing, enthusiastic man who loved sports and surrounded himself with his seven children and their families, the elder Stratford suddenly became "a grouchy old man, totally unlike himself," his daughter said.
His weight dropped to 98 pounds because he had no appetite. With all his activities reduced, "we thought he was just sitting there waiting to die," Barbara Stratford said.
In 1989, the family enrolled the Orange man in a tacrine trial and "there was a very dramatic change," Barbara said. "He went to family gatherings, went back to church and crowds didn't bother him anymore. He started eating again and looked healthy instead of drawn and old. He kind of got his life back."
He died in May from pneumonia brought on in part by his Alzheimer's, but his family is grateful for the three years of lucidity provided by the drug.
The cause of Alzheimer's is still unknown, but most researchers believe that it is probably a combination of genetics, environmental factors and aging, which can combine in different proportions in different people.
The role of genetics has come to the forefront with discoveries made in the last few years.
Last fall, four teams of researchers independently reported that they had identified a genetic defect in families in which Alzheimer's develops at an early age, typically in the 30s and 40s. This defect is located in a specific area of chromosome 14--one of the 23 pairs of chromosomes that carry the complete genetic blueprint of a human--but no one has yet identified the precise gene involved. Experts are excited about this defect because it is present in more than 60% of the families and because chromosome 14 has also been linked to late-onset Alzheimer's.
But the most unexpected and, in many ways, the most exciting genetic discovery involves a gene on chromosome 19. Like the gene on 14, its discovery was announced in October, 1992, and the announcements have since been dubbed the "October surprise."
Roses and his colleagues at Duke University reported that the gene for a protein called apolipoprotein E (ApoE) on chromosome 19 is strongly linked to late-onset Alzheimer's. That was unexpected because, although the ApoE protein is involved in the transport of cholesterol in and out of cells throughout the body, it had never been associated with the brain.
Every individual has two copies of the ApoE gene, one from each parent. Roses' team found that there are three slightly different forms of the gene, called ApoE 2, 3 and 4. Roses found that an individual's risk of developing Alzheimer's depends on which forms he or she inherits.
Roses found that a person with two copies of the ApoE 4 gene is about 15 times as likely to develop Alzheimer's as a person with no copies of it, while someone with only one copy of ApoE 4 is about five times as likely. The genes also affect the age at which the disease develops. About 20% of those with no copies of ApoE 4 develop Alzheimer's by age 75. In contrast, 60% of those with one copy of ApoE 4 and 90% of those with two copies develop Alzheimer's by that age.
Roses' results were initially greeted with a great deal of skepticism but have subsequently been replicated in several different laboratories around the world. "There is almost universal agreement now about the importance of ApoE in Alzheimer's," according to Dr. Robert Katzman of UC San Diego.
Researchers had no idea, however, how variations in ApoE could cause the disorder until Roses and Dr. Warren Strittmatter of Duke presented a bold new theory at a Society for Neurosciences meeting earlier this month. Their theory focuses on the tangles in the brain rather than the plaques that have drawn the attention of most Alzheimer's researchers.
They believe that the tangles result from the destruction of minute channels, called microtubules, that carry nutrients throughout brain cells. ApoE 3 is critical in holding the channels together, much like ties stabilize railroad tracks.
In their test tube studies, Roses and Strittmatter showed that ApoE 4 is not nearly as effective as ApoE 3 in stabilizing the microtubules. Eventually, they fall apart, leading to the death of the brain cells and the formation of the tangles.
Their discovery is a landmark in the study of Alzheimer's, they believe, because it could lead to the first treatment to prevent the onset of the disorder. They believe that it should be possible to design simple drugs that will mimic the action of ApoE 3. "The fact that we don't have to correct something that's wrong, but just have to add something that is not there, adds great potential for therapy," Roses said. "It would be like giving Vitamin C to treat scurvy."
But, Berg cautioned, "not everyone is as enthusiastic as he is."
"Parts of it (Roses' theory) are no doubt true," said Dr. Dennis Selkoe, a prominent Alzheimer's researcher at Brigham and Women's Hospital in Boston, echoing the views of many. "But it's . . . going to take a lot of work to prove. There are a lot of biological questions that it leaves unanswered."
While scientists are trying to prove it, much other work continues apace. Researchers are following up many leads toward potential new drugs to treat Alzheimer's. Tacrine, trade-named Cognex, is so far the only drug approved by the Food and Drug Administration. The majority of researchers argue that it is useful only for some Alzheimer's victims. Unfortunately, there is no way to identify those who will benefit.
Dr. Victor Henderson of USC reported at the recent neuroscience meeting that women who have taken estrogen replacement therapy have a lower incidence of Alzheimer's and that the symptoms of those who do develop it are less severe. That result is "very provocative," said Dr. Zaven Khachaturian, head of Alzheimer's research at the National Institute on Aging, "but it is a very preliminary report that needs to be verified. . . . One of the attractive features is that estrogen doesn't have much of a safety issue, so trials can be organized rather quickly."
Another drug that has recently shown promise, according to researchers from the University of British Columbia, is indomethacin, which is widely prescribed for the treatment of arthritis. They studied it because a variety of research suggests that inflammation plays a role in Alzheimer's.
Dr. Patrick McGeer and Dr. Joseph Rogers reported in August that in a small, six-month study conducted in Sun City, Ariz., 24 patients given indomethacin showed an average 1.3% improvement in memory at the end of the study. In contrast, 20 patients given a placebo (sugar pills) showed an average 8.4% memory loss.
"The most important point is that this is the first trial of a treatment for Alzheimer's disease that is directed at arresting neuronal death," McGeer said. The team is now conducting a second trial in 120 patients.
At least 15 other drugs are also being studied, including three compounds similar to tacrine, a fatty substance called lecithin, a leprosy drug called dapsone, a dietary supplement called acetyl-L-carnitine and seligiline, a drug that is used to treat Parkinson's disease. None of these drugs in trials have shown promise of being a major breakthrough, researchers agree.
Max Weigand is one of the patients receiving Mentane, a drug similar to Cognex, in clinical trials. Weigand, a pianist who lives in North Hills, developed Alzheimer's in 1989 at the age of 73.
"He was very irritable and confused all the time--a complete personality change," said his wife, Rosario. "And he lost the ability to play the piano."
Max Weigand began taking Mentane only three months ago, "but I have already seen a lot of nice changes," she said. "The drug moderates everything. His behavior is better now. . . . The old Max is coming back."
Pharmaceutical companies also have an important new tool for seeking other Alzheimer's drugs. No natural animal model for Alzheimer's exists other than in primates, which are too expensive to use for early drug screening. But researchers have developed new models by inserting genes for beta-amyloid into rodents. The hope is that excess production of the protein would produce symptoms of the disease.
Three such animal models were announced with great fanfare in 1991, but some of the initial work could not be replicated and none of the animals developed severe brain damage characteristic of the disease. Although those animals are being used for drug screening, researchers have higher hopes for two new animal models reported at the neuroscience meeting by two Bay area companies, GenPharm International of Mountain View and Athena Neurosciences of South San Francisco.
"It's very impressive how each of these advances has 'turned on' the field," Berg said. "Every time a new development is reported, all of a sudden, we have 100 more scientists looking at its implications." And the more scientists that are involved, he said, "the sooner we'll find an answer."
A Reason for Alzheimer's?
A radical new theory says that Alzheimer's disease results when nerve cells are not able to nourish their extremities, and die.
HOW IT USUALLY WORKS:
* Nutrients are normally pumped through minute channels called microtubules, whose structures are stabilized by the binding of a protein called tau.
* In most healthy individuals, the functioning of tau is assisted by another protein called ApoE 3.
IN MANY ALZHEIMER PATIENTS:
* More than two-thirds of Alzheimer's victims have a different form of protein, called ApoE 4.
* ApoE 4 cannot help the protein tau stabilize the microtubules, so they eventually fall apart and Alzheimer's results.
SOURCE: Warren Strittmatter, Duke University Medical Center