Solving the Alzheimer’s Puzzle
Ongoing research pieces together causes of the brain-wasting disease, meaning treatment is that much closer

By Anne Mullens

Peter and Geri Hinton knew something was happening to Peter’s brain one lovely summer day nine years ago when the Victoria couple were sailing off Vancouver Island.

Peter, then 76 and a lifelong sailor, had been a naval officer, becoming a base commander at both Victoria and Halifax before retirement. Their 11-metre sloop was his second home. That is why what happened that day was so out of character.

"He was below deck for a long time, banging around, and then he stuck his head out and said, ‘I can’t remember where the depth sounder is,’" recalls Geri of her husband’s bewildering inability to find the device fixed in its usual place in the cockpit.

Puzzles of the past year suddenly began to make sense: Peter’s trouble with words, his difficulty following plots in books, his misplaced items. "That’s when we both knew we had to see someone to get him assessed.

I was almost certain it must be Alzheimer’s disease," says Geri, a former nurse and the then director for the British Columbia government’s Office for Seniors.

For Ted and Pat Sayer, now of Prince Albert, Sask., the symptoms of the fatal, degenerative brain disorder had a similar slow and puzzling onset. Ted noticed that Pat, in her mid-60s, was anxious and reluctant to read the lesson at their Anglican church, which she had done for years. Pat was diagnosed with Alzheimer’s disease in 1999 and continued her duties as a marriage commissioner in Regina, presiding over about 130 weddings a year. Prompted by their worried daughter, Ted sat in on a few weddings. "She was making errors in the ceremonies --forgetting the bride or groom’s name or repeating part of the service."

For Douglas Kearn, 66, of Toronto, memory impairment is in the earliest stages. He has trouble with words and, sometimes, simple physical tasks such as doing up his shirt. His memory troubles come and go. "Sometimes I have no difficulties at all," he says. "At other times I am struggling, I can’t think and I am full of anxiety."

Douglas has been diagnosed with mild cognitive impairment and told he has an 80-percent chance of developing Alzheimer’s within ten years. His mother, at age 77, died of the disease, as did his grandmother and aunt. "Sometimes I am full of fear that my path will be like my mother’s," says Douglas. "That upsets me. At other times, I live in hope something will be found."

Unlike Peter Hinton and Pat Sayer, whose Alzheimer’s has steadily progressed, Douglas’s outcome may indeed be different. Rapid research advances are offering hope that the disease’s unrelenting, brain-destroying course may be altered.

"It is not some pipe dream that there will be a treatment, it is just a matter of time," says Dr. Paul Fraser, professor of medical biophysics at the University of Toronto. "People in the Alzheimer’s field, in general, can see an end to this now; we are going to solve this." Fraser is a key part of a world-class team, led by Dr. Peter St. George-Hyslop at the university’s Centre for Research in Neurodegenerative Diseases, that has made over the last decade a number of significant breakthroughs in the genetics and proteins associated with the disease.

Dr. Pat McGeer, a leading researcher in British Columbia, agrees. "One day very soon Alzheimer’s disease will be as rare as polio," says McGeer. "We now know the targets--the molecular pathology of the disease--and we are aiming at them." McGeer is a director of the new Pacific Alzheimer Research Foundation, which in 2006 received a $15-million provincial government grant.

Around the world, scientists are racing to find individual drugs, drug combinations or even a vaccine to disrupt the destructive process. For a disease so long shrouded in mystery, the progress in understanding in the last few years, says Fraser, "has been like going from here to the moon."

We are hearing the first true note of optimism in the history of this fear-inducing disease that now affects some 290,000 Canadians such as Peter Hinton and Pat Sayer. With an estimated 500,000 more Canadians projected to be diagnosed with the disease by 2031, the optimism couldn’t come at a better time.

Plaques and tangles mar brain of German woman

It was exactly 100 years ago, in 1906, that German neurologist Alois Alzheimer described what he had seen in a recently deceased female patient, Auguste D. At age 51, she could no longer write her name without prompting, was unable to run her household and had signs of increasing disorientation and progressive impairment of memory, judgement, decision making, language and physical skills.

To Alzheimer, she seemed prematurely senile. She was too young to be showing symptoms of the dementia then thought to be a normal part of aging. He called it pre-senile dementia. Her symptoms got worse until she was comatose. When she died at 55, he had her brain shipped to him for examination.

When he saw slices of the brain under the microscope, three features struck him. The brain itself was severely shrunken. Secondly, the brain tissue revealed a strange accumulation of a peculiar substance. Thirdly, inside the brain’s neurons, or nerve-signal transmitters, were stringy tangles of another substance that looked like gnarled twine. These substances, which we refer to as plaques and tangles, are now considered the two essential features that distinguish Alzheimer’s disease from other neurological disorders.

For over 50 years, however, the symptoms of Alzheimer’s were thought to be a normal part of aging, and a true disease only in people who had it before age 65. Those sufferers represent five to seven percent of cases. They have familial Alzheimer’s, explains Dr. Jack Diamond of McMaster University and scientific director for the Alzheimer Society of Canada.

By the 1960s, however, scientists began to realize that the plaques and tangles were not normal even in the elderly and that an insidious disease process was occurring.

Not all dementias are Alzheimer’s, notes Dr. Howard Feldman of the University of British Columbia. All cases of Alzheimer’s show an accumulation of the two substances. Over the last two decades attention turned to them.

Aging remains the biggest risk factor: One person in 20 over the age of 65 develops the disease, one in four over 85. A risk factor for early onset is a genetic family history. Risk factors for late onset include high blood pressure, stroke, heart disease, diabetes, previous head injury and being female.

Understanding "amyloid" and "tau"

Imagine the process of solving the Alzheimer’s picture as researchers struggling with a gigantic, complex jigsaw puzzle. The first puzzle pieces, the nature of the plaques and tangles discovered in the 1980s, put the edges around the picture. Subsequent genetic discoveries began to fill in other parts. With each advance, attention could be turned to filling in the next part of the puzzle as it links to the pieces already in place. The more the picture emerges, the faster the rest can be filled in.

The first major breakthrough in 1984 was the discovery, by a U.S. team, that the plaques consisted mostly of clumped protein fragments called beta amyloid. Another U.S. team decoded the molecular structure of the tangles in 1986 and found it to be a protein called tau.

Decoding the structure of the proteins paved the way for discovery of the various genes that were the blueprints for these toxic proteins. By mapping the DNA from specific sets of families with early-onset disease, researchers discovered various genes one by one. A German-led team found the first associated gene in 1987. In 1995 a University of Toronto team found another two key genes.

Mutations in any of these genes are directly linked to early Alzheimer’s disease. Since not all affected families have mutations in these known genes, "it suggests more genes are yet to be discovered," says Fraser. In addition, scientists found a gene in 1992 called Apo-E4 that increases the risk of developing Alzheimer’s disease in later life. Other genetic discoveries regarding tau and its creation have shed light on tau’s role in Alzheimer’s disease and other dementias.

Finding the first genes enabled researchers to create an animal model for the disease. For decades, Alzheimer’s research was hampered because only humans get the disease, and it is difficult, and often unethical, to do basic research on humans. By transferring the genes into mice, amyloid plaques could be made to clump in mouse brains, enabling easier experimentation--and speedier discoveries.

By 1997 drugs were becoming available, first Aricept, then Exelon and Reminyl. Called cholinesterase inhibitors, they increase the availability of acetylcholine in the brain, an important chemical in the transmission of nerve signals. The drugs temporarily improve the symptoms of the disease, says Diamond, but after six months or so the disease resumes its progression.

In short, two decades of research have created an Alzheimer’s picture called the cascade hypothesis. It looks something like this: We all have amyloid in our brain, usually getting cleared and discarded. Then some trigger combined with aging prompts a change--a genetic mutation, perhaps, a virus, a head injury, or subtle brain damage caused by heart disease or stroke. Suddenly too much amyloid is made or is not cleared away fast enough. This causes the amyloid to build up, which leads to tau accumulation in the neurons. As a result, transport of chemicals is impeded and nerve cells die.

At first the signals in the brain are simply disrupted, impairing memory creation and retrieval--and in this stage drugs such as Aricept can help. As more and more amyloid and tau build up, however, more neurons die, the brain becomes inflamed, tissues atrophy, and eventually, the whole neural network grinds to a halt like a highway network seized in gridlock. The whole process probably takes years to unfold, starting long before symptoms appear.

"If we can stop the accumulation of amyloid," says McGeer, "we can stop the disease."

Compounds eradicating disease in mice

Researchers around the world have found more than 30 different compounds that can retard, halt or prevent amyloid buildup in mice or else speed up its clearance.

"We don’t know whether any of them will do the same for humans," says Fraser, who was part of a University of Toronto team led by Dr. JoAnne McLaurin that announced a promising new agent in June 2006. A compound called cyclohexanehexol, or AZD-103, stopped beta amyloid accumulation in mice and reduced their symptoms.

The compound is in Phase I of clinical trials. Others are in Phase II. In Phase II a treatment’s effectiveness is tested in groups of 100 to 300 people. Then, if it still holds promise, it will move to Phase III clinical trials on up to 3,000 patients with a control group. Neither patients nor clinical researchers will know who is getting the treatment until the end of the trial.

"It will take a couple of years for results," says Fraser, "but these Phase III findings are going to come out one after another, and we will see what is best."

"Don’t delay"

Results can’t come soon enough for Leo Ferrari of Fredericton, a philosophy professor at St. Thomas University, and his wife, Lorna Drew. Leo, 78, was diagnosed with Alzheimer’s in 2003, but symptoms of confusion and forgetfulness probably started appearing as early as 1998. "It was hard to tell as I’ve always been a bit of an absent-minded professor," says Leo.

The couple wrote a book, Different Minds,* describing their side-by-side perspectives. Leo charts the strange, disturbing process in his brain, Lorna, the stress and difficulties she experiences watching her husband decline.

They have a strong message for others who may have early symptoms of the disease: "Don’t delay; getting early diagnosis and going public with the disease is really, really important," says Lorna. "There is nothing to be ashamed of."

Douglas Kearn agrees. "I was in denial at first," he says. "You don’t want to acknowledge the symptoms, but that just delays getting help."

With the first possibly effective treatments coming on stream, with a host of new drugs in clinical trials, now, more than ever is the time to come forward.

The panoply of dementias

While 64 percent of all dementia is Alzheimer’s disease, other diseases or substances can cause mental confusion, memory loss or physical deterioration.

The right diagnosis is important as some dementias are treatable or reversible, says Dr. Howard Feldman, professor and head of neurology at the University of British Columbia, who specializes in Alzheimer’s disease and other dementias. Now the availability of drugs that can stabilize symptoms, and other drugs that are in clinical trials, makes it even more important to get an early, correct diagnosis.

In years gone by, there was little a doctor could do except provide social and medical support, says Feldman.

Compared to other dementias, Alzheimer’s has a distinctive set of slowly increasing symptoms that, with careful medical histories combined with cognitive tests, can give an accurate diagnosis 80 to 90 percent of the time," says Feldman.

Dementias caused by infection and drug interactions are usually identifiable as you may be fine one day and sick the next" and have telltale rapid onset.

Other dementias include:

Vascular dementia. Most common after Alzheimer’s, it’s caused by single or multiple strokes in the brain and can exist on its own or in combination with Alzheimer’s. Onset can be sudden or gradual. Smoking, obesity, diabetes and high blood pressure are risk factors. Treatment consists of reducing risk factors and using medication to improve blood flow to the brain. Drugs such as Aricept are showing some effectiveness.

Prion diseases. Abnormal proteins that can be transmitted in tissue, prions are the culprits in rare diseases such as Creutzfeldt-Jakob disease (CJD). CJD is a rapidly progressive form of dementia that has four forms--sporadic, arising in people 45 and older with no risk factors; in families with a genetic mutation in the prion; from exposure to tissue infected with the disease; and through consumption of beef products contaminated with mad cow disease. No treatment.

Lewy body dementia. Like Alzheimer’s plaques, Lewy bodies are unusual, protein-filled structures in the brain that cause some neurons to die and other neurons to become impaired. This dementia can coexist with Alzheimer’s and Parkinson’s disease and shares symptoms with both diseases. Cause unknown. No cure.

Frontotemporal dementia (Pick’s disease). Unlike Alzheimer’s, Pick’s affects only the frontal and temporal lobes of the brain. Symptoms arise most often in those ages 50 to 60 and include sudden change of behaviour or personality and problems with speech, but memory may be spared at first. Confusion and dementia worsen as the disease progresses. Cause and risk factors not yet known. No cure.

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10 signs of Alzheimer’s

Is it Alzheimer’s or just a "senior moment"?

While everyone has memory lapses from time to time--forgetting to serve the salad, being unable to recall a person’s name, suddenly forgetting what you came into the room to do--Alzheimer’s symptoms are more frequent and extreme. The Alzheimer Society of Canada (www.alzheimer. ca) lists ten warning signs:

1. Memory loss that affects day-to-day functioning, especially forgetting recent events.

2. Difficulty performing familiar tasks you’ve done most of your life, such as preparing a meal.

3. Problems with language such as frequently forgetting simple words or substituting inappropriate words.

4. Time and space disorientation such as getting lost on your own street.

5. Poor or diminished judgement such as making inappropriate clothing choices.

6. Problems with abstract thinking such as being unable to recognize what numbers in a chequebook mean.

7. Misplaced items, particularly putting things in inappropriate places, such as an iron in the freezer.

8. A combination of behaviour or mood changes such as going from calm to tears to anger for no apparent reason.

9. Changes in personality, such as becoming suspicious, withdrawn, fearful or acting out of character.

10. Loss of initiative such as becoming very passive and requiring cues or prompts to become involved.