Untangling Alzheimer’s

Five years ago, Mary McKinley began to notice that simple tasks at the office where she worked were taking her longer than usual to complete. Ringing telephones and clacking keyboards distracted her. She became easily confused and couldn’t sit at her desk for longer than an hour without taking a break outside, away from the din. At first she thought there was a problem with the air in the building. But none of her co-workers were complaining.

The confusion persisted, so McKinley, 63, found a new job in a quieter environment at a lawyer’s office, not far from her home in Picton, Ontario. One morning, she forgot how to turn her computer on. Not long after, while making bread, she poured flour into the sink instead of the breadmaker. Putting in dentures – something she’d done every morning for years – suddenly proved baffling. “At that point,” she says, “I knew something was screwy.”

McKinley booked an appointment with her doctor and underwent a battery of tests, including a mini-mental state examination – 11 questions that physicians commonly use to screen for dementia. The doctor asked McKinley to state the day’s date and the location of his office. He asked her to fold a piece of paper in half and put it on the floor. When he asked her to count backward from 100 by sevens, her brain seemed to freeze; she couldn’t remember how. McKinley says the doctor’s eventual diagnosis – Alzheimer’s disease – came as a complete surprise to her. “I didn’t know much about Alzheimer’s, except that it affects old people,” she told me one sunny afternoon in October. “And I didn’t feel that old.”

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Dr. Peter St. George-Hyslop didn’t know much about Alzheimer’s disease, either, when he was a second year medical student at the University of Ottawa. He recalls examining a woman who exhibited no physical problems but appeared confused and couldn’t remember why she had come to see a doctor in the first place. “It was very intriguing to me,” says St. George-Hyslop, now a U of T professor and leading authority on Alzheimer’s. “Everything worked, except her faculties of higher reasoning.”

A talented medical student who graduated at the age of 21, St. George-Hyslop went on to train in neurology and internal medicine and do post-doctoral work in molecular genetics at Harvard Medical School. There, he began investigating the genetic underpinnings of Alzheimer’s, a cruel and, as of yet, incurable disease that gradually robs patients of their memory and all higher thought processes. St. George-Hyslop was intrigued by the gooey plaques and tangled fibres – first observed by the German physician Alois Alzheimer more than 70 years earlier – that develop in the brains of those with Alzheimer’s. In 1990, he returned to Toronto, to U of T’s newly established Centre for Research in Neurodegenerative Diseases (CRND), to continue his work in genetics and study how these plaques and tangles form. Today, he leads the research efforts of more than 60 CRND staff as they hunt the genetic causes of – and potential treatments for – some of humanity’s most debilitating brain illnesses, including Alzheimer’s.

It’s an immense undertaking. Research into the genetic causes of a disease is an extremely complex, time-consuming and competitive process that involves gradually narrowing down the location of one or more genes from the estimated 20,000 that comprise the human genome. In his book, The Selfish Gene, Oxford University evolutionary biologist Richard Dawkins compares the human genome to 46 rolls of ticker tape – corresponding to the 46 human chromosomes. On these ticker tapes is written an individual’s entire DNA code, comprising some three billion coding units called “base pairs.” Dawkins defines a gene as a section of code on one ticker tape, with nothing to clearly mark the end of one gene and the start of another. One can understand, then, why locating a specific gene is so difficult.

By the time St. George-Hyslop arrived at CRND, the race to be the first to identify a major gene responsible for Alzheimer’s was in full swing. In 1992, scientists narrowed the search to a large section of Chromosome 14. Through some clever detective work and painstaking analysis over the next few years, St. George-Hyslop and his team eventually identified a single mutation in a previously unknown gene on Chromosome 14 as a cause of early-onset Alzheimer’s. The gene, which they called “presenilin 1,” heralded CRND’s arrival as a significant international force. “That really was a fiercely competitive piece of research,” recalls St. George-Hyslop, noting that several other academic groups and biotech companies had been hunting for the same gene. Being first confers a range of advantages: international accolades and attention, and the likelihood of greater research funding. “In terms of getting grants, it’s much better to say, ‘I was first,’” says St. George-Hyslop, who seems to appreciate such accolades more for their help in advancing the centre’s mission than any sense of personal reward. “I like an interesting problem and a neat solution. I prefer not to be publicly outlined.”

CRND’s discovery of presenilin 1 (and, a few months later, presenilin 2) helped guide the direction of subsequent research into Alzheimer’s disease. As St. George-Hyslop explains, the presenilin genes produce proteins that initiate the disease. He understood that by learning how these proteins interact with each other and the neurons they destroyed, he and his team might be able to point the way to new Alzheimer’s treatments. They might, for example, be able to propose how to stop the body from producing the amyloid-beta protein that causes the toxic plaques, remove it from the brain or prevent it from aggregating into plaques. Then, they might be able to provide new hope for the millions of people worldwide – and the 300,000 in Canada – who suffer from Alzheimer’s disease.

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Doctors advise Alzheimer’s patients to stay as active as possible, since studies show that physical and mental stimulation may help slow the disease’s inevitable progression.

McKinley, who enjoys doting on her 10 grandchildren, couldn’t imagine not living an active lifestyle. “If you sit and dwell on it, and think ‘Poor me,’ you’ll go downhill fast,” she says. Instead, McKinley, now retired, writes a weekly blog and still manages to bake bread every other day. Last summer, she and her husband, Jim, cycled the country roads outside of Picton on a tandem bike. For a while, she hosted an online chat room for Alzheimer’s sufferers and caregivers run by the Fisher Center for Alzheimer’s Disease at Rockefeller University in New York City. She still spends several hours a day online, researching her condition and sharing information about it with some of the more than 600 people she’s met in the chat room in the past two years. Gregarious by nature, McKinley keeps a detailed record of everyone she meets. “I love chatting with people,” she says.

So far, McKinley hasn’t experienced the debilitating short-term memory loss that affects most Alzheimer’s patients. In fact, this oddity cast some doubt on McKinley’s diagnosis. Dr. Sandra Black, the head of neurology at Sunnybrook Health Sciences Centre in Toronto, tested McKinley and told her she has a form of frontotemporal dementia, a condition similar to Alzheimer’s. After running additional tests, Black changed her mind and now believes the original diagnosis is correct. “It seems to depend on what my brain is doing on any given day,” shrugs McKinley, who also suffers from poor balance, an early indication of Alzheimer’s.

Medications have eased McKinley’s symptoms. She takes Aricept and Ebixa – drugs that temporarily reduce the telltale signs of Alzheimer’s but don’t halt or slow its progression. Since starting the two drugs about a year-and-a-half ago, “things have gotten better and better,” she says.

Still, the disease has forced McKinley to adapt. She gave up driving after a scare while overtaking a farm tractor on the road to Picton. (She noticed an oncoming truck and couldn’t decide whether to slow down or speed up to pass.) She doesn’t enjoy dinner parties; the loud, overlapping conversations confuse her. McKinley uses a walker outside the house to keep her balance. Inside, she steps carefully, placing one hand on the furniture, a wall, the door, to steady herself. Despite facing daunting challenges and a grim prognosis, she refuses to succumb to anger or self-pity. “This is just a new part of life, another journey,” she says, philosophically. “You just do things a little differently: a little more slowly.”

Like many Alzheimer’s patients and their caregivers, McKinley watches closely for news of drug developments. She tells me about a potential new drug that’s designed to prevent the amyloid plaques from forming in the brain. “A few people say that it will reverse symptoms,” she says, hopefully. “There’s a lot of talk in the chat room about that.”

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From the moment a scientist isolates a molecule with intriguing therapeutic potential to the day Health Canada approves it for public use is a long and tortuous journey with many potential dead-ends. The whole process often takes a decade or longer, and the vast majority of potential drugs don’t make it out of the testing phase. Earlier this year, Quebec-based Neurochem announced plans to market Alzhemed, its leading Alzheimer’s candidate drug, as a nutraceutical (a dietary supplement) rather than a drug after testing in patients failed to show conclusive positive results.

Patients and caregivers grasp at any hint of hopeful news, which is why St. George-Hyslop is careful to be realistic about CRND’s efforts in the area of potential therapies. Yes, pharmaceutical companies are testing some interesting possibilities as a result of the centre’s research, but no, there’s nothing that actually slows the disease in Alzheimer’s patients – yet. He prefers to steer attention to the centre’s investigations into the biology of how the disease progresses.

Since St. George-Hyslop and his team identified mutations in the presenilin genes as a cause of Alzheimer’s, some of the centre’s researchers have been seeking to understand exactly what the presenilin genes do and how mutations in these genes lead to the disease. As is often the case with scientific investigation, things are significantly more complex than they first appear.

Paul Fraser, one of CRND’s principal researchers, has worked closely with St. George-Hyslop since arriving at the centre in 1991. Fraser earned a PhD in biochemistry at U of T and did post-doctoral work in neurobiology at Harvard Medical School. He has spent a lot of time investigating the presenilin genes, which, it turns out, regulate not just a single protein in the brain, but a whole family of proteins involved in producing amyloid. Scientists have uncovered four major proteins, says Fraser, but there are “probably many more that impact on each of those four.” In 2006, Fraser was part of an international research team led by the University of Toronto that uncovered TMP21, a naturally occurring protein in the brain that inhibits the production of amyloid.

Figuring out what all these proteins do and how they interact will be a time-consuming process, requiring years of lab work. But the knowledge should yield some promising avenues for new therapies. Teasing out exactly how TMP21 inhibits amyloid, for example, and why it doesn’t affect other functions in the presenilin complex could provide a blueprint for an effective drug. (Presenilin governs several important signalling processes in the brain, and previous attempts to block or slow the production of amyloid have resulted in serious complications in patients.)

On another front, the centre has conducted research that could lead to an Alzheimer’s vaccine. In 2000, St. George-Hyslop and his team showed that a vaccine worked in a mouse model of Alzheimer’s. The vaccine went into clinical trials, but the trials were stopped when some of the immunized patients developed brain inflammation. Since then, CRND’s researchers have shown what may have caused the toxic effect. This work has served as a basis for the development of new, refined vaccines.

Last year, CRND researchers published a paper in Nature Medicine describing a molecule that prevents the amyloid protein from aggregating into toxic plaques. The centre tested the molecule in a mouse model of Alzheimer’s and found it improved the mice’s cognitive ability. CRND has licensed the potential drug to Toronto’s Transition Therapeutics for testing in humans. In August, Transition announced the successful completion of Phase 1 clinical trials (to test the drug’s tolerability in healthy humans) but has yet to start Phase 2 trials (to test tolerability in people with Alzheimer’s). At this early stage of development, the drug is still a long shot to succeed.

Despite all of these intriguing therapeutic possibilities, St. George-Hyslop believes an effective Alzheimer’s treatment may still be many years away. He compares our understanding of the disease today to where cancer research was 20 years ago. The first generation of anti-amyloid drugs are being tested and, until the results are in, “all bets are off,” he says. Although confident that new therapies will slow the disease and may even induce a slight improvement in patients, he’s doubtful that removing the amyloid plaques is the end of the story.

St. George-Hyslop is particularly concerned about the tangled fibres that form inside diseased neurons. Although it’s possible that treating the amyloid will be all that’s necessary to bring about improvements in Alzheimer’s patients, the amyloid may, in fact, have caused tangles to form or irreversibly damaged neurons in other ways. In other words, simply removing amyloid from the brain, or preventing it from aggregating, may not be enough. (Scientists now believe that amyloid builds up in the brain for years, or even decades, before patients start to show symptoms.) St. George-Hyslop worries that the tangles, which are deadly to neurons, may cause the disease to progress until they are stopped. “That’s a major concern at this point,” he says.

Research into any disease proceeds in three phases: first, understanding its causes and how it works; then, designing treatments to stop or prevent it; and finally, repairing the damage it has caused. So far, most Alzheimer’s research falls into the first category; work on the second phase, designing treatments, is just beginning. However, CRND is now looking for researchers for the final stage – studying how neurons are born, move around the brain and connect with each other – in the hope of being able to repair brain damage.

Last spring, St. George-Hyslop won the $5-million Premier’s Summit Award, which recognizes world-class research in Ontario. He will use the money to recruit researchers interested in neuronal repair. This type of study is in its infancy, but could have huge implications not only for people with Alzheimer’s disease, but for individuals who have had a stroke or who have a brain tumour or mental retardation, says St. George Hyslop. “Even in a simple animal, such as a worm or fly, understanding these processes is going to be very difficult. In humans it will take a decade or two.”

As with all research endeavours, money is crucial – and not always easy to come by. For the bulk of its funding, CRND relies on peer-reviewed research grants and donations from individuals and non-profit societies interested in neurodegenerative diseases. Although a $5-million grant is considered unusually large in Canada, St. George-Hyslop says it would be fairly typical in the U.S. With its funding limits, CRND must choose its projects carefully. “Right now we’re constrained to pursuing a number of main ideas, but there are many other projects we could do in six months or a year if we had the resources,” he says. In the meantime, the difficult lab work continues. St. George-Hyslop doesn’t encounter Alzheimer’s patients on a day-to-day basis, but the centre has relationships with many of the families who have donated DNA for studies. He’s aware that they’re grateful for the groundbreaking research at CRND, but he’s not prepared to accept any plaudits – not until an effective treatment is found. “We haven’t accomplished our goal yet,” he says.

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McKinley understands that her condition will worsen. She remains hopeful, however, that the work of St. George-Hyslop and other researchers around the world will lead to an effective treatment and, one day, a cure. In the meantime, McKinley knows that, despite the drugs she is taking, she will gradually lose the ability to do many of the things she likes, such as baking bread and cycling with her husband. I ask her if she fears for the future. She shakes her head, smiles. “I’m loving life and I have a very good feeling with God,” she says. “I have no problem moving on.”