Aug 01 2008

Promising Alzheimer’s Treatment

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Several interesting papers have come out of the recent International Conference on Alzheimer’s Disease, but the one to make headlines was that of Professor Claude Wischik. He has been doing research into tau protein, the protein that forms the neurofibrillary tangles that make up one of the pathological hallmarks of Alzheimer’s disease and is a cause of the death of neurons. He presented data on a new drug, Rember (methylthioninium chloride) that in a phase II trial of several hundred subjects reduced the progression of the disease by 81%.

Alzheimer’s Disease (AD)

AD is a neurodegenerative disease – a category of neurological disorders that involve the death of one or more populations of cells within the nervous system. Their causes are largely unknown, but are likely different among the various degenerative diseases and there is likely multiple mechanisms even within individual syndromes. If the word “disease” is attached to the name of a neudegenerative disorder, that implies that there are specific features (usually pathological) that distinguish it and a specific pathophysiological entity. For example, Parkinsonism is a category of neurological disorders that have the same signs and symptoms. Parkinson’s disease is one such disorder that has specific pathological findings on brain biopsy (although is also has a unique clinical feature – response to dopamine – and so that is how the diagnosis is typically made).

Likewise, AD is a disease (actually it is further divided into two diseases, an inherited form and a sporadic form) – it can only be diagnosed specifically by looking at brain tissue under a microscope. Therefore most people walking around with the diagnosis of Alzheimer’s disease really have a diagnosis of Alzheimer’s type dementia. Dementia is any chronic illness involving global loss of cognitive function, especially memory. Alzheimer’s type means that other causes have been ruled out. That’s it – dementia with a negative workup for a specific treatable cause is Alzheimer’s type dementia, which is often conflated with Alzheimer’s disease, because most of the time they are in fact the same thing. But the diagnosis of AD is usually not confirmed (if at all) until autopsy. Brain biopsies are generally not done because it is an invasive procedure and it will not effect treatment.

By the way – this is why it is very important to insist on an autopsy for any relative who dies with a diagnosis of AD – because they really have a diagnosis of Alzheimer’s type dementia, and autopsy is your one opportunity to get a firm pathological diagnosis, which is important for your family medical history. You owe it to the next generation in your family – do it.

The primary pathological findings in AD are neurofibrillary tangles and plaques. Tangles are, as the name implies, tangle of tau protein. Plaques are more sheet-like in form and are comprised of another protein, beta-amyloid. In the pictures below, the top one shows tangles and the bottom one plaques.

Translational Research

The new study by Wischik is an excellent example of what is called translational research – the application of new basic-science knowledge to clinical treatments.  This may seem obvious – and it is – but because researchers typically focus on either basic-science research or clinical research, specific effort needs to be made to tie the two together in the same research program.

It represents one of the primary strengths of science – all scientific knowledge works together. Our understanding of AD leads directly to our ability to treat it. This is also why to some degree it is useful to allow basic-science researcher to simply research what they find interesting, without a specific tangible goal in mind. In other words, researchers do not have to be looking for a cure for AD, but rather can simply follow their curiosity about the disease, how it works, and what is happening. The knowledge that comes from satisfying the researcher’s curiosity is likely to lead to something tangible, if history is any guide.

AD Treatments 

Current treatments for AD are largely symptomatic. They primarily inhibit the enzymes that break down acetylcholine – the main neurotransmitter involved in memory. Therefore there will be more acetylcholine available in the synapse between two neurons, the strength of the signal will be increased, and memory function will get a little boost. The effects of these drugs are measurable, but modest. They do not restore lost brain cells nor to they alter the course of the disease. I often read discussions of these drugs that report that they delay the progression of the disease, but this is not true. The measured decline of AD patients on these drugs will be less, because they will test better while taking the drug. But as soon as they come off the drug they fall back to their previous curve of progression. Actual progression has not been altered – just temporarily masked by a symptomatic treatment.

This is actually a common mistake in research – a possible confounding factor that can lead to a false conclusion. The academic community, however, is well aware of it. Basically, a drug that has a symptomatic benefit for a disease could give the false impression that it is slowing the progression of the disease if the symptomatic effects are not taken into account. This likely happened in Parkinson’s disease with the drug selegeline.  It was first touted as a drug to slow the progression of Parkinson’s disease but was later found to have symptomatic benefit. When this was taken into account the apparent benefits to delayed progression vanished.

There is one drug for AD, Namenda, which is a glutamate inhibitor. This likely also just has symptomatic benefit, but a small benefit for slowing progression is also possible. Still, while measurable, the benefits are modest.

There is therefore a huge need for a drug that clearly and significantly slows the progression of AD, and this new drug promises to be just that.  The data so far is from a phase II clinical trial, which is a trial in humans with the disease in question, but it is small and preliminary. Such studies are used to justify and help design phase III trials, which are considered definitive clinical trials. This means we are still about 4 years away from Rember hitting the market, at least. This depends upon how quickly a phase III trial can be completed, but of course also on the results. If the results are clearly positive, and no adverse events crop up, it can get through the FDA quickly. But the FDA can be sticklers – they may demand a second trial, or more research to explore possible side effects reported during the study. Drugs can be delayed for years or never make it to market.

If Rember pans out, as everyone hopes it will, it will hopefully be just the beginning of a multi-pronged approach to AD.  This is the direction that clinical research is heading with many neurodegenerative diseases – trying to find a cocktail of many drugs, each of which has a modest benefit but combined has significant benefit. For AD we may eventually have Rember to untangle the tangles, another drug to dissolve the beta-amyloid plaques, another drug to reduce stress on neurons by inhibiting glutamate, and another drug to enhance the action of acetylcholine. There may also be other targets of interest as well.

Because AD tends to strike late in life (although the familial form is younger in onset), and the disease typically progresses over years, slowing down the progression of the disease may allow most people with AD to live a normal lifespan with minimal symptoms – even without a complete cure.

Science Rules

In conclusion I would like to do a completely shameless metaphorical victory dance for science. Science is our most powerful tool for understanding the world and thereby improving our lives. Mysticism, superstition, magical thinking, and all the nonsense that makes up the bulk of alternative medicine does nothing for humanity. Magic isn’t real, science is. This new research is reductionist, materialist, naturalistic science at work. And thank goodness for it.

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