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Research advances from the International Conference on Alzheimer's Disease (ICAD) - July 2009
Comments by Dr. Jack Diamond, Scientific Director, Alzheimer Society of Canada
Introduction
The International Conference on Alzheimer's Disease (ICAD) has now changed from a biennial meeting to an annual meeting. This is a sobering thought when one considers the progress of research into treatments for a prolonged and variable condition such as Alzheimer's disease (AD). For example, following a drug's very first successful testing in animals, it can take up to 10 years before the drug can then be prescribed. What advances can we expect, then, between 2008 and 2009?
Animal models of Alzheimer's disease
It's essential, before a human clinical trial can be initiated, that any proposed treatment be first shown to have some success against an appropriate animal model of AD. An astonishing feature of this ICAD was the number of reports (more than 40) dealing with new such models. It's becoming clear that we don't yet have the perfect animal model of AD, so the introduction of new ones is to be applauded. Currently, the most-used models are genetically engineered mice, mice which have been "transfected" with one or even two of the human genes responsible for bringing about the rare Familial Alzheimer's Disease (FAD). FAD is the same as the common sporadic form of AD, but the disease is essentially triggered by abnormal, inherited, genes. These "transgenic" mice, like humans with AD, have impaired learning ability and memory. Scattered throughout the brains of these mice are the hallmarks of AD, microscopic deposits called plaques, and additionally in one such transgenic mouse, the characteristic tangles within nerve cells. In some of the mouse models newly identified suspect genes were deleted or added, and in others, hormones and other drugs were administered, anticipated to make the mouse AD more like the human version, especially in regard to an accumulation of A-beta in the brain.
In some instances, instead of using the whole animal, researchers tested selected drugs to see if they would repair diseased nerve cells taken from the brains of animal models of AD and kept alive in nutrient fluids in a dish. This "in vitro" approach allows researchers to make quick tests of many drugs over a relatively short time period, and is the method of choice by drug companies. Finally, a couple of reports described an exciting new genetic animal model involving rats. This is exciting because the rat is traditionally a more easily studied animal than the mouse especially where behaviour is concerned, although it is by no means so accessible to genetic engineering.
Problems addressed at the ICAD
Unfortunately, over the last few years a number of treatments that appeared to work well on transgenic mice models of AD, particularly in reducing plaque numbers in the brain and improving their behaviour, were disappointing when tested in people. Of special note, the first AD vaccine worked well on mice (vaccine reports are discussed below), but some people with AD treated with the same vaccine developed a potentially deadly inflammation of the brain, causing an immediate stoppage in vaccine trials. Mice and humans are different, and we shouldn't be too surprised if even the same disease-producing genes lead to different outcomes in the two species. There are almost certainly gene variants contributing to the AD abnormalities in humans that are simply not present in the genetically engineered mice. Finally, AD in humans is heavily associated with aging, and most of the AD models used relatively young adult animals; this may have to change to increasing the use of older animals.
Drug trials
Despite the caveats made above, a number of drug studies were reported in which the signs of AD in transgenic mouse models were successfully reduced. Moreover, a few drugs reported last year as entering, or already within, Phase 2 or Phase 3 human clinical trials are continuing to look promising; side effects were not threatening, and a slowing down of the progress of the disease in its early to middle stages was significant (it's rare for people in the advanced stages of AD to be included in these disease modifying drug trials). The focus of most of the drugs reported at the ICAD was still A-beta, the protein that accumulates in the AD brain, poisoning the nearby nerve cells, and hypothesised as triggering the development of the tangles inside them, a principal cause of their sickness and eventual death. The progressive build-up of A-beta protein leads to the appearance of the characteristic plaques of the AD brain, already mentioned above.
One class of drugs reduces A-beta levels by inhibiting the enzyme which splits off the A-beta from a larger parent molecule. Yet other drugs work by preventing the A-beta molecules from sticking together in twos or threes to form the oligomers, now regarded as the form of A-beta most toxic to nerve cells. The good news is that at least some of the drugs which are working well in Phase 3 trials could be approved by government health agencies within 3-5 years, and allowed to be prescribed to people with AD.
Vaccines
Vaccines induce (or actually provide) antibodies which combine with the A-beta molecules, masking their toxicity and facilitating their elimination by cells of the immune system. Despite the setback described above for the first vaccine trials, the promise of vaccines still fuels one of the most active areas of therapeutic research, and there were no fewer than 19 reports at the 2009 ICAD of new studies in this field. Vaccines are definitely a future hope.
Dimebon
The drug Dimebon was the subject of a new report at the ICAD. Dimebon caused some excitement earlier in the year when it was reported as improving thinking and memory and indeed a variety of behavioural functions in people with early to mid-stage AD who had been treated with this drug for at least 12 months. At ICAD Dimebon continued to look promising. Slight improvements, even a bare slowing down, in the disease progress is important. Indeed, even no obvious improvement is significant, because in the absence of treatment an overall decline in their status would be almost inevitable. It now seems that Dimebon may actually bring about improvements in people with AD. Dimebon protects tiny organelles inside the nerve cells from the degeneration they suffer as the disease progresses; these organelles are called mitochondria, and they're essential for the cell to use oxygen properly.
Dimebon has already been tested (mainly in Russia), with a modest degree of success, as an antihistamine agent for allergies, for heart disorders, and for a variety of infections. This means that its side effects, and tolerated dosages, are already known, which speeds up its testing for Alzheimer's disease. Dimebon could become an important new therapy for Alzheimer's disease within the next 5-10 years.
Preventing the disease from developing in the first place
Could the same drugs that slow down the progress of AD reduce one's chances of developing the disease? This is a more difficult issue; to find the answer could mean diligently following a continuously drug-treated population of normal, probably elderly, people for many years to find out if fewer of them developed AD in comparison to untreated people (the incidence of AD in the latter population is already known from published figures). This kind of long-term study has been used with some success when the particular therapy is more of a feature of lifestyle rather than a drug, and is the basis of preventative therapy for AD.
Diet and Exercise
There were 14 reports in the 2009 ICAD showing that both modest exercise, and adherence to a Mediterranean-style diet (nuts, fruit, vegetables, fish, and low salt), were effective in reducing the risk for AD and slowing down its progression, in comparison with people whose lifestyle was clearly different in these two respects. Definitely encouraging news! Supplements of DHA, the omega-3 fatty acid found in fish oil, failed to slow the progression of AD in a clinical trial with 402 study participants, but did cause some modest improvement in another trial. So omega-3 fatty acids remain controversial. Now these lifestyle reports have appeared before, but because the numbers of persons involved in such studies are almost invariably too small to satisfy the statisticians, the more often the findings are replicated, the better. A sedentary lifestyle and a regular consumption of red meat and sweets are definitely to be discouraged!
Quality of Life
The ICAD has traditionally not been a focus for Quality of Life (QoL) research, not because QoL studies are less important than biomedical ones, but largely because QoL is well represented in a number of other scientific meetings, especially those specifically dealing with age-related health issues generally. Traditionally, the annual meeting of ADI (Alzheimer's Disease International) has always had a special focus on QoL. Nevertheless a respectable number of QoL papers and posters were presented at the 2009 ICAD. Of particular interest were a number of reports further confirming the significant health risks of caregivers (a high prevalence of mental health problems was described in one report). Another report very convincingly described how an increase in specialisation of long term care facilities and a higher staff/resident ratio were associated with lower agitation levels and less usage of antipsychotic drugs. Other reports addressed the question of how best to measure QoL, in regard both to the person with AD and the caregiver. QoL research clearly continues to flourish.
A final thought on ICAD goals
An issue which can be anticipated to take a larger place in future ICADs is the use of drug and behavioural therapeutic approaches in combination. This has been a relatively neglected area. Animal research, backed by a few relevant human observations, shows that both lifestyle and drugs can significantly influence connectivity in the brain. This finding impacts memory, cognition, and mood. For this reviewer, the ultimate solution to the successful management of dementia is inevitably going to require a combination of pharmacological and behavioural therapies, ideally in association with an appropriate lifestyle. This strategy could also be a major approach to the prevention of dementia in later life.
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