Conference on Clinical Trials on Alzheimer's Disease

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Almost invariably when Alzheimer's disease is mentioned, be it in the media or in medical reports, the words "for which there is no cure" appear with depressing regularity.

The Conference on Clinical Trials on Alzheimer's Disease (CTAD), the first of its kind, held in September 2008 in the historic School of Medicine in Montpellier, France, marks a significant change in the attitude implied by these words.

As this Conference made clear, within five to seven years we may well have treatments for Alzheimer's disease that could halt, or certainly significantly slow down its progression, a position justifying the active search for treatments that could go further, and reverse the effects of the disease.


A Report by Dr. Jack Diamond, Scientific Director, Alzheimer Society of Canada


So what actually was presented at this Conference? Well, as always, the items selected for report will be ones that appeared to this attendee to speak most directly to the concerns and hopes of the Canadian Alzheimer community, both those with the disease, as well as their family members and caregivers. For general interest, one new development with potentially important implications will also be included.


Quality of Life (QoL)

The first eye-catching issue was the demonstration by a number of presenters that the evaluation of the severity of Alzheimer's disease, its diagnosis, and the success of treatments, now has to include assessments of the quality of life (QoL) experienced by the person with the disease.

This point may seem obvious to those touched by the disesae, but there is still a persisting bias against it among some medical researchers, with some notable exceptions, among which Canadian clinical scientists are prominent.

In practice, the assessment of Alzheimer's disease and how it responds to treatment is based largely on how the individual scores in tests such as the Alzheimer's Disease Assessment Scale (ADAS-Cog), and the Mini-Mental State Exam (MMSE). But to caregivers, how well the individual fares in performing the mundane activities of daily life is at least as important as the more cerebral activities involved in memory and cognition, and on a day-to-day basis perhaps even more important.

A number of the reported clinical trials showed beyond any doubt that including evaluations of QoL along with the conventional measures of memory and cognition does not adversely skew the overall clinical assessment of the dementia, but actually adds a dimension that is important in its own right. At this Conference there was marked enthusiasm for this approach, which hopefully will make QoL a regular item in the evaluation of Alzheimer's disease and of the effectiveness of administered treatments.


Combination Therapy

Also convincingly demonstrated in a number of the reported clinical trials was the increased therapeutic value of using multiple interventions (always two, so far) rather than single ones. This ranged from using two medications together such as Aricept and memantine, to combining a medication, say Aricept, with a non-pharmacological treatment ("cognitive rehabilitation"), the latter involving a variety of verbal and pictorial learning sessions supervised largely by clinical psychologists or their equivalent.

One problem associated with using more than one drug at a time is the discomfort of pharmaceutical companies faced with sharing a clinical trial of their drug with that of another company. As the evidence for the increased success of such combination therapies mounts, however, they are coming round to this approach.

Combination therapy could require more resources and cost more than monotherapy, but as presented at this conference, its effectiveness is so obvious as to make it a priority in the treatment of Alzheimer's disease.


Biomarkers of Alzheimer's disease

A particular emphasis in some of the clinical trials reported at this Conference was on the use of ‘biomarkers' of the disease. For years clinical scientists have sought Alzheimer's disease-related changes that could be readily detected in easily accessible tissues such as blood, urine, and also in the less easily accessed cerebrospinal fluid (CSF). The CSF is the fluid that bathes the brain and the spinal cord, and can be obtained with little difficulty and hazard by lumber puncture.

At this Conference there was no question that the most accurate and revealing biomarkers were changes in CSF levels of the proteins, or modifications of these proteins, that are principal components of the 'plaques' and the 'tangles' found in the Alzheimer brain. Not only did the observed changes in the CSF correlate excellently with the presence or absence of Alzheimer's disease, but the evidence suggests that the changes might reveal the subset of people with Mild Cognitive Impairment (MCI) destined to proceed to the full blown Alzheimer's disease.

Unexpectedly, the same biomarkers were detected in a small group of elderly people without dementia and not diagnosed with MCI, and often they were carriers of the apoE4 gene. The researchers suggested that these findings were not 'false positives' (identifying Alzheimer-like changes in genuinely normal people), but in fact were picking up people in very early stages of the disease, before either dementia or MCI had appeared. Nevertheless people with undiagnosed MCI could be in this category, since it is now clear that people with diagnosed MCI can have plaques and tangles in their brains many years prior to the ages when they would be anticipated to develop Alzheimer's disease.

The results of these trials make a strong case for including a search for CSF biomarkers in people in whom the diagnosis of Alzheimer's disease is unclear. As genuine treatments for Alzheimer's disease come along, it's important to establish their use as soon as possible, so early diagnosis is becoming a front line activity. In this the search for CSF biomarkers will play a significant role.


A Novel Therapeutic Approach

In the early stages of Alzheimer's disease, the readily diagnosed symptoms are due to impaired communication between sick nerve cells in the brain. This communication occurs at the junctions – called synapses – between nerve cells. Cholinesterase inhibitors such as Aricept and Exelon are effective because they help maintain this communication, but only up to the point when the nerve cells are just too sick to support any form of communication between them (it may take years to reach this limit, which is soon followed by the death of these cells).

A novel clinical trial first presented at the 2008 International Conference on Alzheimer's Disease (ICAD) also targeted synaptic functions in the Alzheimer brain but took a different approach from that of the cholinesterase inhibitors. At the Montpellier conference, the scientific basis of this approach was described in full by the researcher whose insights and studies over very many years led to this new treatment now being promoted commercially, although it seems not yet to be available in North America.

Without going into the scientific details, suffice to say that the treatment is a cocktail of naturally occurring compounds, though somewhat concentrated here, which are taken by mouth. The net results in the body are an increased production or availability of: i) some of the chemicals required to maintain the physical structure of the synapses; ii) the chemical substances involved in transmitting messages across the synapses; and iii) the chemicals which oppose the inflammation associated with degeneration of synapses in Alzheimer's disease.

It was clear from the results reported that the treatment did improve cognition and memory in a number of people in the very early stages of Alzheimer's disease, without obvious adverse side effects. It is not implied here that the Alzheimer Society of Canada is sanctioning or sponsoring the commercial product which provides this treatment cocktail, activities which we scrupulously avoid. The intent is principally to underline that, in accordance with our promotion of the healthy brain, these new scientific findings constitute further evidence that dietary choices can significantly affect the susceptibility to and/or the progression of Alzheimer's disease.

The specific ingredients of the cocktail in question (for the interested, uridine monophosphate, choline, the omega 3 fatty acids EPA and DHA, phospholipids, B vitamins and antioxidants) occur, though in lesser concentrations than in the commercial preparation, in such foodstuffs as beets, eggs, fish oil, and any foods rich in vitamins B, C, and E.


Limitations in Animal Models of Alzheimer's disease

In earlier days the only available model of Alzheimer's disease were (i) the aged animal, and (ii) animals with surgical lesions that reduced important functions in brain regions involved in memory and cognition. The use of aged animals is clearly unsatisfactory given that aging is a risk factor for the disease, but does not represent the disease itself. Animals with lesions were also unsatisfactory because the lesions could at best only approximate some of the defects in Alzheimer's disease, and the abrupt loss of function differs starkly from the slowly developing changes that characterize the disease proper.

This situation changed dramatically as genes responsible for the rare hereditary form of Alzheimer's disease became identified and were transferred into mice using genetic engineering techniques (transgenic mice). As these genes were expressed (i.e. began to function) both the brain pathology of the disease (first the 'plaques', and in more recent mouse models, the ‘tangles' too), and cognitive and memory impairments appeared at the mouse level.

The situation now is that human clinical trials begin only after the treatment being tested has been shown to effectively reduce the manifestations of the disease as it appears in transgenic mice. At the Montpellier Conference a number of successful phase 1, 2 and 3 clinical trials (these phases were described in the earlier Research advances from the International Conference on Alzheimer's Disease (ICAD) report) of drugs with coded names were presented, adding to the ever-increasing battery of putative treatments which could be appropriate for administering to Alzheimer patients within five to seven years. As at ICAD, the target of most tested drugs was the toxic beta amyloid protein which accumulates in the Alzheimer brain.

That being stated, the fact is that we are seeing increasing numbers of anomalies and differences in the effects of the new drugs and vaccines being tested in humans compared to the preceding tests which generally worked so well in the transgenic mouse models. These differences were discussed at the Montpellier conference.

Can we explain these discrepancies? Are they going to reduce the importance of the animal models? Well, the latter question is easily answered; we are obligated to conduct preliminary trials with animal models, but perhaps they can be further improved. For example, the present transgenic mouse models of Alzheimer's disease should be tested when the animals are aged, even though the mutated Alzheimer genes the animals carry are certainly expressed in the young animal.

It's becoming increasingly clear that we do not know enough about the effects of aging on the brain, but it seems that at least some of the effects are very variable among the population, such that chronologically equal-aged people (or animals) may have quite different levels of brain age. The expression "he (or she) is old before their time" implies this often encountered disconnect between chronological age and brain age. Indeed, it seems that certain specific effects associated with aging – not necessarily seen in all individuals, nor in all individuals of the same age – could be critical in the development of Alzheimer's disease.

We have a lot to learn here.

There is more. Some aged humans with no signs of dementia have multiple plaques in their brains, though perhaps fewer tangles than normally seen in Alzheimer brains. Relatively young Down's syndrome individuals (say in their 40s) can have typical Alzheimer brains without an accompanying dementia. And now we read of a human vaccine study in Ireland in which the density of brain plaques was reduced exactly as occurred in animals, but unlike the animals, the humans continued to display an unchanged level of dementia!

So the transgenic animal models of Alzheimer's disease are not perfect. Perhaps the interdependence of certain genes and the rate and extent of their activation, properties increasingly recognized by geneticists, differ between animals and humans; mice and men are not the same!

Whatever the answer, another stumbling block is emerging in the search for a cure. But hopes remain high, and rightly so. The future is still more promising now in regard to a cure for Alzheimer's disease than at any other time in our history.