Alzheimer's Battle

Alzheimer's Battle

At first, the effects are almost imperceptible: a man or woman cannot find keys or forgets the name of a loved one. As Alzheimer's disease continues to destroy nerve cells in the brain, the incidents become more frequent - and more troubling. Along with progressive memory loss, the person may become moody and restless, and begin wandering or pacing, often in the middle of the night. In the late stages of Alzheimer's, the patient becomes bedridden and needs 24-hour-a-day care before dying, often from pneumonia. Doctors and scientists have long understood this inexorable downhill march - and have been powerless to slow it, let alone halt it. Now, however, science is providing glimmers of hope as researchers around the world, including those doing leading-edge work in Canada, announce new findings about the disease almost every week.

It could be years before a diagnosis of Alzheimer's is anything other than an eight- to 10-year death sentence. But as scientists and health professionals gain a better understanding of the disease - everything from the underlying risk factors to what sets it in motion and its complex biochemical processes - they are gaining insight into potential preventives, treatments and cures. The research has already yielded one new prescription drug, with several more soon to follow, that can help delay the onset of symptoms in the early stages. One goal now is to extend that symptom-free period.

While far from a cure, the delaying tactic still offers benefits, both to the individual who can live a normal life for longer, and to society as a whole. "If we can delay the onset of symptoms by five years, we will decrease the number of persons with Alzheimer's by half," says Dr. Serge Gauthier, director of the Alzheimer disease research unit at the McGill Centre for Studies in Aging in Montreal. "If we delay the onset of symptoms by 10 years, we will reduce the number affected by Alzheimer's in one generation by 75 per cent." That reflects the harsh actuarial fact that, in those five or 10 years, many potential Alzheimer's sufferers will have died of other - likely less devastating - causes.

According to 1999 numbers projected from a landmark 1991 Canadian Study of Health and Aging, some 316,500 Canadians, most of them over 65, suffer from one or another form of dementia. In the past, those exhibiting the symptoms - loss of memory, judgment and reasoning, and changes in mood and behaviour - were often simply labelled senile. But today, senility is no longer considered a normal part of aging, and is instead seen as a sign of disease. Alzheimer's is the leading cause of dementia, accounting for about two-thirds of the cases, while others, including frontotemporal dementia and Creutzfeldt-Jacob disease, account for most of the rest. A further 230,000-plus Canadians suffer from incurable, sometimes fatal, neurological disorders that do not necessarily result in dementia, but do extract a heavy toll on the body.

With Canadians living longer than in generations past and with the leading edge of Canada's 10 million baby boomers now in their early 50s, the numbers of those with Alzheimer's is expected to grow dramatically. The Alzheimer Society of Canada projects that, unless there is a breakthrough, more than 750,000 Canadians will have the disease by 2031. That number is based on studies worldwide indicating one in 13 people over 65 and one in three over 85 are affected with the disease. The general population is beginning to grasp the enormous implications. A Léger & Léger poll of 1,500 Canadians released in January shows Alzheimer's is now the third-most-feared disease as people age, trailing only cancer and heart troubles. The survey was sponsored by Pfizer Canada Inc., the Kirkland, Que.-based manufacturer of Aricept, the first prescription drug specifically targeted at Alzheimer's.

That sense of alarm is spurring research in many fields. Neuroscientists, psychiatrists, biochemists, occupational therapists, geneticists and epidemiologists are all involved in a wide range of investigations. Working within their own fields or on multidisciplinary teams, they have developed, and sometimes discarded, many new theories. Few now believe there is a single cause of Alzheimer's, concluding instead that it is caused by a combination of factors, genetic and environmental.

Aluminum from pipes and pots, once a principal suspect, has largely been dismissed as a cause, says Gauthier. But other risk factors are still being examined. Several studies have shown that those who have at least a Grade 10 education - which could indicate a more developed brain or reflect a healthier socioeconomic environment - have a lower risk of developing Alzheimer's symptoms than those with less schooling. Other studies suggest that those who have had a bump to the head have an increased chance of developing the disease.

Meanwhile, other scientists are debating a possible relationship between the female hormone estrogen and Alzheimer's. While a study published last month in the authoritative Journal of the American Medical Association showed estrogen replacement therapy did not slow the progression of the symptoms, other researchers have concluded that post-menopausal women who take the hormone have a decreased risk of the disease. And new research even raises questions about whether nicotine - a villain when in tobacco products - can play a beneficial role in neurological diseases. Doctors told a conference of the American Association for the Advancement in Science in Washington in late February that six Alzheimer's patients treated with synthetic nicotine experienced fewer symptoms.

Many researchers believe, however, the answers they are seeking lie in the body, possibly within the brain itself. On that front, advances in basic research are providing a solid underpinning. "We are learning so much about the microbiology of the brain," says Dr. Ian Whishaw, professor of neuroscience at the University of Lethbridge in Alberta. "We know much more than we did 10, or even five years ago." Whishaw and a colleague, Dr. Brian Kolb, are the co-authors of Fundamentals in Human Neuropsychology, the standard text translated into five languages and used in universities around the world. The pace of discoveries means the book will be updated next year, the fifth time in 20 years. That knowledge is helping scientists understand the complex cascade of events that starts killing cells in the hippocampi, two tiny, sea-horse-shaped parts of the brain associated with memory, and eventually leads to cell death throughout the cerebral cortex, the so-called grey matter of the outer layer.

Advances in genetic research are also helping to unlock some of Alzheimer's mysteries. So far, researchers have discovered four genes that can lead to the disease, including two that Dr. Peter St George-Hyslop and his team at the University of Toronto identified within a two-month period in 1995. The genes are responsible for a rare form of the disease called Familial Autosomal Dominant Alzheimer's. FAD, which is clearly passed from one generation to the next, accounts for five to 10 per cent of Alzheimer's cases. While people with FAD may develop symptoms as young as 30, the disease appears similar to the more common, so-called sporadic Alzheimer's in every other way. Thus by studying the rare form, says St George-Hyslop, director of the university's Centre for Research in Neurodegenerative Diseases, scientists hope to learn more about Alzheimer's in general. Meanwhile, the hunt is on to discover other genes linked to the disease. "I suspect in the next few years," says St George-Hyslop, "we will know a lot more about the genetics."

Still, not everyone who has a genetic predisposition goes on to develop the disease. So other researchers are trying to find out what triggers Alzheimer's in some people but not others. At Queen's University in Kingston, Ont., scientists are conducting basic research into amyloids, types of protein deposits that can build up both inside and outside cells. They show up in connection with about 20 diseases, the most common being Alzheimer's and diabetes. According to Dr. Robert Kisilevsky, professor of pathology and biochemistry at Queen's, amyloids are composed, in part, of proteins commonly found in the body. But for reasons that are still being investigated, the proteins are processed abnormally and become noxious. The long-term goal of those researchers is to find ways to interfere with the formation of the amyloids. That way, says Kisilevsky, they may be able to interrupt the fundamental process of the disease itself, rather than just treat its symptoms.

The writings of ancient Greek physicians indicate that Alzheimer-like symptoms have plagued mankind for millennia. But modern understanding of the disease is less than a century old. In 1906, German scientist Aloïs Alzheimer described an autopsy he performed on a woman who died after experiencing an unusual form of amnesia. As well as finding that many of her brain cells had disappeared, he made two startling discoveries in the remaining cells: dense bundles of fibres, called tangles, and other peculiar formations, eventually called plaques. Those changes became the hallmarks of the disease that now bears his name.

These days, doctors can make a clinical diagnosis of Alzheimer's by taking an in-depth personal history of the patient, usually provided by a family member, and conducting a few simple cognitive function tests. Studies suggest they are accurate about 90 per cent of the time. Still, a post-mortem finding of the unique tangles and plaques in a diminished brain remains the only way to be 100-per-cent positive the patient had Alzheimer's and not another form of dementia.

New evidence shows that the plaques - which some researchers relate to amyloids - and tangles are wreaking havoc in the brain long before the patient shows any signs of the disease. So far, there is no treatment for any form of dementia. But once treatments become available, getting the diagnosis right will become especially important. That has prompted researchers, including those at the University of Toronto, to work on developing new brain imaging and biochemical tests. "In truth, the issue is not whether you can make a diagnosis of Alzheimer's," says St George-Hyslop, "but can you make the diagnosis very, very early, before there has been any major, irreversible change. Once brain cells die, in general they don't come back."

Meanwhile, doctors are trying out ways to help patients even as they wait for more answers from researchers. Until recently, the only drugs in the arsenal were those like antidepressants and anti-hallucinogens that counter only some of the side-effects. Then in 1997, after seven years of development, Pfizer launched Aricept in 20 countries, including Canada. The prescription pill, covered by provincial drug plans only in Ontario, Manitoba and Alberta, lessens, or at least stabilizes, some of the problems associated with the early to middle stages of the disease. It does that by inhibiting the enzyme that breaks down acetylcholine, which helps to transmit nerve impulses in the brain.

Still, as Gauthier and others note, Aricept is not a cure for Alzheimer's because it does not change the underlying course of the illness. The next kind of drug likely to become available, he says, will help the brain repair itself. Those medications are aimed at boosting the proteins essential to the growth and maintenance of the brain. One such drug, code-named AIT082, will undergo a large-scale clinical trial this spring across Canada, Gauthier said.

A note of frustration creeps into Dr. Patrick McGeer's voice as he describes the attempts to find funding for an untested avenue of research. In the mid-1980s, he and his colleagues at the University of British Columbia in Vancouver were examining the brain cells of former Alzheimer's patients when they became intrigued. They saw the same kind of molecules that had classically been associated with inflammation elsewhere in the body, but had never before been reported in the brain. Other than some money from the Alzheimer Society, "we got absolutely no support from Canadian sources," says McGeer, now professor emeritus of psychiatry at UBC.

They did, however, find funding in the United States and Japan and carried on with their research. Since they published their results in 1987, researchers around the world have replicated their findings. "If people can't confirm your findings," McGeer says, "the line of inquiry dies. If it flourishes, more and more people get into it."

The UBC team next theorized that those taking anti-inflammatories for other reasons would be protected to some extent against Alzheimer's. That is exactly what they found when they conducted epidemiological research using data from the Canadian Study of Health and Aging. Those with rheumatoid arthritis suffered significantly less Alzheimer's than the general population, they discovered. But the UBC researchers still encountered skepticism. "When we published our fundamental findings," recalls McGeer, "it was dismissed as a flawed study." Once again, however, their work has been replicated, this time in more than 20 epidemiological studies worldwide. And clinical trials are under way to see whether the new generation of anti-inflammatories, such as Celebrex, can delay the progression of Alzheimer's disease.

But perhaps the strongest indication that McGeer's findings have gained mainstream credibility is the part he will play when Alzheimer's researchers from around the world gather next month in Stockholm. McGeer is to be the keynote speaker. When it comes to Alzheimer's - or any disease - today's controversy may contain the seeds of tomorrow's cure.

Is it Alzheimer's, or Not?

It is important to see a doctor if warning signs of Alzheimer's disease are present. (Some may apply to other forms of dementia.)

Memory loss that affects day-to-day function

While it is normal to occasionally forget appointments, colleagues' names or phone numbers, then remember them later, a person with Alzheimer's may forget things more often and not remember them later, especially things that have happened more recently.

Difficulty performing familiar tasks

Busy people may occasionally leave the carrots on the stove and remember to serve them only at the end of the meal. People with Alzheimer's may be unable to prepare any part of a meal, or forget they ate it.

Problems with language

Everyone has trouble finding the right word sometimes, but a person with Alzheimer's may forget simple words or substitute inappropriate words, making sentences difficult to understand.

Disorientation of time and place

While it is normal to forget the day of the week or your destination - for a moment - people with Alzheimer's disease can become lost on their own street, not knowing how they got there or how to get home.

Poor or decreased judgment

People may sometimes put off going to a doctor for an infection but will eventually seek medical attention. People with Alzheimer's may not recognize the infection as a problem or go to the doctor at all. They may also dress inappropriately, wearing heavy clothing on a hot day.

Problems with abstract thinking

From time to time, people may find balancing a chequebook difficult. Someone with Alzheimer's disease could forget completely what the numbers are and what needs to be done with them. A person with Alzheimer's may not understand what a birthday is.

Misplacing things

Anyone can temporarily misplace a wallet or keys. A person with Alzheimer's may put things in inappropriate places: an iron in the freezer or a wristwatch in the sugar bowl.

Changes in mood or behaviour

Everyone becomes sad or moody from time to time. Someone with Alzheimer's can exhibit rapid mood swings - from calm to tears to anger - for no apparent reason.

Changes in personality

People's personalities can change somewhat with age. A person with Alzheimer's can change dramatically, becoming extremely confused, suspicious or withdrawn. Changes may also include apathy, fearfulness or acting inappropriately.

Loss of initiative

It is normal to tire of housework, business activities or social obligations, but most people regain their initiative. A person with Alzheimer's may become very passive, requiring cues and prompting to become involved.

Maclean's March 13, 2000