Alzheimer's Disease: a Detective Story

This seems an unlikely candidate for a whodunit, yet determining the cause of a disease like Alzheimer’s is, in many ways, like a detective story. Like any good story, there is a long trail of complicated interweaving story lines before you get to the final resolution. There may be a list of very plausible suspects at the start, and the job of the detective, as the story unfolds, is to look beneath the surface, examine, sift through and analyse the evidence and determine who was responsible.

The Alzheimer’s detective story began in 1906 when German neuropsychiatrist Alois Alzheimer was the first to make certain observations during the post-mortem study of a woman who had had dementia. He noted deposits, ‘Plaques’, of what he called ‘a peculiar substance’ scattered all over the brain, and ‘dense bundles’, or Tangles, of fibrils within brain cells, many of which had died. The Plaques seemed to be part of aging, but the Tangles seemed to have a much closer link to dementia. The resolution of the story may well be revealed exactly a hundred years later. The story so far …

To begin with there were numerous plausible causes, but by now they have been whittled down to four suspects. First is the Amyloid Plaque, the lead research culprit for the last 20 years, but with little to show in terms of tangible clinical benefit. It has been estimated that the Amyloid theory has absorbed at least £100 million in research funding per annum for the last 20 years. The two very limited clinical trials to date (30 and 78 subjects respectively) gave surprisingly weak results. It had been hoped that an Amyloid treatment would impact on the real underlying mechanism of the disease.

Second, there is the cholinergic defect. People with Alzheimer’s have reduced levels of a neurotransmitter called acetylcholine in their brain. Acetylcholine is one of the chemicals that nerve cells use to communicate. This too was discovered about 20 years ago, and has led to the development of drugs which aim to inhibit the breakdown of acetylcholine. The world market for these acetylcholinesterase inhibitors is about £3 billion per annum. The benefits are real, but on the whole, modest and temporary. Only about 1 in 5 cases seem to be "responders". They are “symptomatic” treatments, not “disease-modifying” treatments, but they are all we have at present.

The third group of suspects is actually a mixed class. There are potential theoretical links to Alzheimer’s disease from almost any conceivable branch of basic cell biology. From hormones, to cell signalling pathways, to gene control systems, to non-specific trophic molecules, to natural scavenger systems, to cell-death pathways. In all of these, it is possible to claim a potential relevance to Alzheimer’s disease. These would not really offer treatment of the disease mechanism, but are more like first cousins of symptomatic approaches. Plant extracts, hormones, homeopathic treatments: who knows?

Which brings us back to the main Alzheimer story. During the period of Amyloid dominance in the research field, the Tangle was regarded as an end-stage marker. In terms of our whodunit, the Tangle seemed to have an alibi. Yes, it was at the scene of the crime, but it had arrived too late to come into the frame as a real culprit.

But that alibi has now been blown. Tangles actually appear in the brain much earlier than had been thought. A German researcher, Braak, has described six stages in Alzheimer’s disease, the so-called Braak Stages 1 – 6. Full clinical dementia appears at about Braak 4. If we take the mid-fifties as an index age, the odds of being at Braak 1 or beyond are about 35%, Braak 2 or beyond – 12%, Braak 3 or beyond – 4%. By the early 70's the figures become: Braak 1 or beyond – 70%, Braak 2 or beyond – 45%, Braak 3 or beyond – 26%. It is now estimated that the process that finally appears as dementia may well begin before age 40.

Tangles are made of an abnormally aggregated form of Tau protein. If we measure the levels of Tangle-Tau protein in the upper brain at Braak 2 and 3, the levels are already significant, and may well be enough to produce early stage symptoms, even if there are no Tangles to be seen in the light microscope! The level of Tangle-Tau protein in the brain is highly correlated with the level of mental impairment, from the earliest symptoms to end-stage dementia.

So the brain is already accumulating Tangle-Tau protein well before Tangles actually appear, and this seems to be very closely linked to mental decline. At the early stages, Tangle-Tau protein is accumulating at the rate of less than 0.1% per day. In the established phase of the disease, this rate is about 1.7% per day. Imagine the build-up of a credit card debt if the compound interest rate were 1.7% per day!

Therefore, we come back to the interesting part of the story. Could we stop the Tangle-Tau protein from accumulating in the brain? It turns out that simply delaying the rate of accumulation would still lead to accumulation. Therefore, the more useful form of this question is: “Can Alzheimer’s Tangles be Dissolved?”. The answer to this is: Yes. We showed in 1996 that this could be done with a prototype drug in the test-tube. The challenge since then has been to develop living models to discover drugs that reverse Tau aggregation in living cells and, more importantly, reverse dementia in Tau-transgenic mice.

The crunch comes with the next question: if we treat people with a drug which dissolves Alzheimer’s Tangles, can we improve their mental functioning and delay progression of the disease? That is exactly where we are now. At the University of Aberdeen, we have obtained permission from the UK regulatory authority (MHRA) and from ethics committees to undertake the first ever human study to test this question. The trial will involve up to 400 subjects recruited from centres in Scotland, England, Wales and Australia. **Only patients in the participating centres will be approached by Principal Investigators who have already been identified, and it will not be possible to take volunteers outside the formal structure of the trial set up in the designated centres. It is a question of the ethics and proper organisation of a fully randomised double-blind placebo-controlled trial. We will start in September 2004, and we expect an answer before the end of 2005.

So, exactly 100 years after his initial discovery, we may be coming towards the end of the particular line of enquiry started by Alzheimer. Unfortunately, research is not like reading a novel. When we are finally overwhelmed with exasperation, we can’t cheat and skip to the last few pages to see whodunit. In the book of research, as in the book of life, we don’t know what is written on the next page.

Professor Claude Wischik, Professor of Old Age Psychiatry, University of Aberdeen

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