Scientists are making headway on research to treat, diagnose, prevent and hopefully even cure this devastating disease. Readers Digest investigates recent progress Source: Readers Digest Australia, July 2009

ALZHEIMER'S: Glimmers of hope

Annette Altree-Williams was in the middle of editing a book when she started muddling her insulin shots for the first time in her life. A diabetic since childhood, Annette mentioned the fact to her doctor and after a number of tests she was diagnosed with Alzheimer’s disease. She was just 54. Five years later, her husband, Steve, has given up his work in Canberra to help her manage her condition. Annette can no longer go out alone, gets lost in shops, and can’t work a computer. Her doctor says her medication, Aricept, is slowing the disease, nevertheless Annette is alarmed at how quickly her mind is failing. “People like me have a lot of life left in us, a lot of great mental capacity, which is diminishing before it’s captured and used. It just seems such a waste,” she says.

Alzheimer’s disease isn’t a normal part of ageing, nor does it affect just seniors. However, old age is a big risk factor and because our population is getting older, the number of people with Alzheimer’s is blowing out. Alzheimer’s Australia believes the number of Australians with dementia will almost double by 2030, to 460,000 costing the health care system $8.2 billion a year.

A range of drugs is now available – including Reminyl, Aricept, and Exelon – to adjust the chemical balance in the brain and stall decline by about a year. A fourth, Exiba, is used for more advanced stages of the disease. The problem with these treatments? They don’t reverse the underlying disease process. Their effect is temporary, and they’re only useful in Alzheimer’s with limited benefits for the other common forms of dementia.

What people with dementia need most is a drug that will reverse their condition – known in scientific circles as a “disease modifying therapy”. With nearly one million Australians involved in caring for a family or friend with dementia, the company that develops such a drug will have a bestseller.

Quest for a cure

Beta amyloid is a sticky protein that exists in the brain. But for reasons we don’t understand, in people with dementia it clumps together to form plaques that kill off brain cells. The more beta amyloid plaques that exist, the more severe the disease.

Perhaps by getting rid of the beta amyloid, you can reverse the disease. That’s the theory behind a slew of clinical trials now underway around Australia and the world.

Several of the new therapies being tested use monoclonal antibodies to hunt out and prevent a build up of amyloid. Wyeth’s drug Bapineuzumab has gone to a phase-three trial involving 4000 patients worldwide – that means it’s been shown in previous trials to help some users and is now being tested on a larger number of patients. Pfizer is starting a phase-two trial, and most of the other drug companies have products in early stages of research.

While it looks like these drugs hold promise, it’s feared they may also carry side effects such as micro hemorrhages in the brain.  Other researchers are trying a different tack: to slow the production of beta amyloid.  One international phase-three trial by Eli Lilly aims to inhibit the enzyme gamma secretase, which can create beta amyloid.  Elsewhere, trials are underway into other enzymes such as alpha secretase, which may stop the amyloid being produced.  One of the most exciting breakthroughs took place in Melbourne last year.  Prana Biotechnology has developed PBT2, which targets zinc and copper in the brain.  The theory is that the ions, or electrically charged molecules, in these metals interact with the beta amyloid and make it accumulate into plaques and become toxic.  An early trial published in the  journal Neuron last year found mice treated with PBT2 had far less beta amyloid in their brains and dramatically improved memory, learning and behaviour, sometimes within hours of being given the drug.  As well as beta amyloid plaques, people with dementia develop “tangles” of protein inside the nerve cells in the brain, which destroy these cells and impair concentration and memory.  Last year, British researchers announced their drug, Rember, could slow the progression of the disease by up to 81% by removing the tau protein, which makes tangles.

Another drug showing promise is Dimebon, an entihistamine that affects the mitochondria, or tiny batteries which power brain cells, and stops them dying.  An 18 month Russian study last year found the drug stabilised the disease in 183 Alzheimer’s patients.

All of these drugs are a way off still:  they must undergo much larger trails to prove that they work and are safe; then they go through a range of regulatory processes before they hit the shelves.  Still, “It’s certain that there will be more-effective medications,” says Glenn Rees, chief executive officer of Alzheimer’s Australia.  “What’s difficult to know is whether it’s three, five or ten years away”.

Diagnosis

Diagnosing dementia is still a tricky process: memory tests don’t pick up the subtle changes of the early stages of the disease and it’s hard to distinguish the symptoms of Alzheimer’s from those of depression, anxiety and poor education.  Dedicated memory clinics, which have access to specialist psychologists as well as advanced imagine techniques, have a 90% accuracy rate in diagnosing dementia.  But even so, most people are already well into their disease by the time it’s diagnosed

“What we need is a biological test based on genes, proteins in the blood or brain imagine,” says Professor David Ames, director of the National Ageing Research Institute in Melbourne.  “In the next decade, if we have an effective early treatment, we would give it to people before they had symptoms.  Then we could really make a big impact on the population.”

Already, better imaging techniques mean doctors can look deep inside the brain to see changes that might indicate if a person will develop Alzheimer’s.  One very hopeful area, Positron Emmission Tomography or PET scans, uses an agent, PIB, that binds to the beta amyloid.  If there’s a lot of beta amyloid in the brain, you can be pretty sure the patient will develop Alzheimer’s.  This is being looked at as part of the large Australian Imaging, Biomarker and Lifestyle (AIBL) Study.  Researchers are using PET/PIB scans to compare beta amyloid levels in a number of patients to work out how predictive they are for Alzheimer’s.  “If the amyloid load is highly predictive, this will be a very useful test,” says Professor Ames.

Tom Valenta knew his wife, Marie, had Alzheimer’s – she’d been diagnosed a year before her PET/PIB scan.  But he was shocked at how graphically the scan showed the spread of the disease.  Coloured in bright yellows and oranges, the areas covered by beta amyloid plaques seemed to dominate the brain.  “My main hope, and I believe it’s a realistic hope, is that (PET scans) will be part of the solution that will prevent my three children from getting Alzheimer’s,” he says.  Valenta is enthusiastic about PET/PIB scans because they can detect the beta amyloid build up before there is any outward sign of behavioural change or memory loss.  “Hopefully in the future my children and others who know there is a family history will be able to go to a clinic just like you’d go for a mammogram or pap smear, have this screen done,” he says, “and if there’s a sign of Alzheimer’s hopefully get a preventive medication.”

But even if they do prove accurate, PET scans cost about $1000 a pop and require patients to be injected with a radioactive tracer.  At the moment they’re only available in two centres in Australia, in Melbourne and Perth.  What’s really needed is a simple blood test.  That’s still a long way off – but 50 years ago no one would have thought you could diagnose high cholesterol simply by testing a drop of blood.

Work’s already underway.  Stamford University recently reported promising results from a blood test that picked up changes in how cells “talk” to each other when Alzheimer’s develops.  Meanwhile, other US researchers have found early signs of Alzheimer’s can be seen in the cerebral spinal fluid 10 or 15 years before the disease actually manifests.

Prevention

We know a lot about what happens during the course of Alzheimer’s – the biological cascade that leads to the emergence of beta amyloid plaques, and how these affect memory and behaviour.  What we don’t know is what kicks off that whole process.  There is a gene that’s common in most people who develop Alzheimer’s after the age of 65.  But that gene is found in a quarter of the population.  So why do some of us get the disease and others don’t?

One theory is that people who go on to develop Alzheimer’s often have the same risk factors as people with cardiovascular disease.  And that’s led to a major Australian finding that may mean thousands of people can prevent Alzheimer’s by watching their blood pressure.  “Often, plaques occur on top of, or really close to, a micro bleed in the brain, and one of the main risk factors for micro bleeds is high blood pressure,” says Dr Michael Valenzuela, a clinical regenerative neuroscience research fellow in psychiatry at the University of NSW.

“High blood pressure in middle age is linked to two and a half times the risk of dementia 20 years later.  If we can reduce blood pressure rates, we can reduce dementia rates.”

Once people have the disease, blood pressure will have little effect: in fact, people with Alzheimer’s tend to have low blood pressure.  But if you’re in your 40s or 50s, it pays to control your blood pressure through diet and exercise, and, if necessary, medication.

Exercise is also a crucial preventative strategy against Alzheimer’s in other ways.  It has a range of positive effects on the brain, promoting the generation of new brain cells (neurogenesis), promoting connections between the brain cells and increasing hormones that control the brain’s function.  “It’s really an incredibly powerful medicine,” says Dr Valenzuela.

But it’s not just physical exercise that’s being looked at.  Research is underway into the role of keeping socially and mentally active – the “use it or lose it” theory.  People who do both these things have lower rates of dementia, possibly because they are placing greater demands at a neuronal level.

The future may hold even more promise for Alzheimer’s prevention.  Ways of stimulating the body’s own immune system to prevent the build up of beta amyloid are being looked at.  If successful, it will mean a vaccine against Alzheimer’s.

Studies into vaccines have been hindered by the side effect of brain inflammation.  But one day, says Dr Michael Woodward, head of aged care at Austin Health in Melbourne, “If immunisation was shown to be safe and effective, it may be possible to give it to people in their 20s and 30s to stop them getting Alzheimer’s.”

Wouldn’t old age be a brighter prospect if that were possible?