Alzheimer's - and the Pharmaceutical industry

Discovering Medicines For Alzheimer's - Introduction

As brain research progressed through the 1980s and 1990s, many different theories for the design of Alzheimer's medicines were proposed. These often drew on difficult concepts in modern molecular biology, but this booklet aims to give a simplified outline of each one and an account of their present status. The main proposals which have led to medicines development are:

1. that Alzheimer's is due to a shortage of the chemical messenger, acetylcholine. Medicines have been made that slow its breakdown and three are now available to patients
   
   
2. that nerve cells can be stimulated to release extra acetylcholine by giving medicines that act on brain targets called M and N receptors
   
   
3. that people with Alzheimer's can be helped by giving them medicines that stimulate other brain targets that play a role in memory and reasoning
4. 
   that the damage to nerve cells and loss of them is due to local inflammation in the brain, in which case, anti-inflammatory medicines may help
   
5. 
   that in some people, the brain over-produces toxic forms of oxygen (ROMs) which cause tissue damage leading to the death of nerve cells
   
   
6. that it may be possible to stimulate the survival or regrowth of neurones by using medicines which act like a nerve growth hormone
   
   
7. that the symptoms of Alzheimer's arise because neurons are damaged by the tangles and plaques found in the brain. In this case, medicines that prevent these structures forming could alter the progress of Alzheimer's
   
   
8. that it might be possible to vaccinate people to prevent plaques forming or to stimulate the body to remove those already formed.

Each of these areas is discussed in more detail below.

Medicines currently available for Alzheimer's

Many medicines are already available to ease the secondary symptoms of Alzheimer's, such as depression, agitation, anxiety and sleep disturbances. These include conventional antidepressants, tranquillisers, anti-anxiety agents and hypnotics which help nursing staff and families to cope with people with severe dementia. However, they are not Alzheimer's medicines in the strict sense and will not be discussed further. Rather, we will concentrate here on medicines that can improve the mental skills of persons affected or enhance their ability to cope with daily life. In later sections, experimental medicines that might in the future slow or halt mental decline will also be considered.

The brains of people with Alzheimer's have reduced levels of the enzyme choline acetyltransferase and the neurotransmitter acetylcholine (ACh) compared to healthy elderly people. ACh is broken down by an enzyme called acetylcholine esterase (AChE) which is found in the brain and other tissues in slightly different forms. If this breakdown could be stopped, it would make the reserves of ACh last longer, with possible benefits. The first medicines assessed for Alzheimer's treatment work in this way and are called acetylcholine esterase inhibitors.

The first of these, tacrine (Pfizer), is available in the USA, but has not been made available in Britain because of possible adverse effects on the liver. First in the UK was donepezil, developed by the Japanese company Eisai and launched here with Pfizer. It has fewer side effects than tacrine, because it is fairly selective for brain AChE and causes fewer unwanted actions in other organs. It also survives a long time in the body, so it can be given just once a day - an advantage in a forgetful person and for those having to care for them. Clinical experience shows that it can enhance mental alertness and activity and improve behavioural symptoms, but has no lasting effect on the underlying progression of the illness. It is of value for some people with mild to moderate Alzheimer's, but not everyone, and eventually their condition deteriorates as the neurons that use acetylcholine die.

Rivastigmine (Novartis) is also selective for brain AChE and can increase ACh levels in the hippocampus and cortex - the very areas where Alzheimer's damage is greatest. It is also chemically different from donepezil, has different properties when it binds to AChE, and does not rely on the liver for removal from the body. For these reasons, rivastigmine has a lower potential for interfering with other medicines that older people may be taking at the same time.

The most recent addition, galantamine (Shire and Janssen-Cilag), was discovered in snowdrop and daffodil bulbs. This was made available at the end of 2000 and trials have shown that it can improve both mental activity and behavioural symptoms. Some people even remain stable or slightly improve after five or six months of treatment.

Perhaps this is due to the fact that galantamine not only blocks ACh breakdown but separately stimulates the nicotinic (N) receptor which is thought to induce neurons to release extra ACh.

Some other compounds of this type are in development, but it would appear that all of them suffer from the potential problem that they will only work if there are sufficient neurons present that use ACh. Truly curative medicines of the future will need to stop the rapid and premature death of these neurons, rather than just acting to preserve the chemical messenger involved.

Percentage decline from normal in choline acetyltrans-ferase in the brain of people with Alzheimer’s

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