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Latest findings on Alzheimer's disease

NORMAN SWAN: In recent weeks, there have been several advances in Alzheimer's disease research, particularly from studies of the possible genes involved - a gene being a segment of DNA on a chromosome which holds the code for a specific protein.

It's not easy stuff to understand but it is giving important information about the substance called 'amyloid' which gunks up the brains of people with the condition. Here with a review of the state of the knowledge to date is expatriate Australian geneticist and writer, Dr Alison Stewart, who is based in Cambridge.

ALISON STEWART: For a long time, it has been known that susceptibility to Alzheimer's has a genetic component, though in most cases other factors, presumably environmental ones, are also important in determining whether someone succumbs to the disease.

But in about 10 per cent of sufferers, there is a very strong family history, and in these families the pattern of inheritance suggests that it is caused by a single gene. In families affected by this so-called familial Alzheimer's, the symptoms often start relatively early in life, when the person is in their forties or even thirties.

A few years ago, affected individuals in some of these families were found to have mutations in the gene that produces a protein called beta amyloid precursor protein, or APP. This seemed very significant because one of the features in the brains of people with Alzheimer's is deposits of a protein called beta amyloid which seem to be fouling up the nerves. Beta amyloid is made from APP. But the excitement about this discovery was tempered by the fact that no mutations could be found in the APP gene in most other patients with the familial form of Alzheimer's.

Recently though, two other genes have been found that can cause familial Alzheimer's when they contain mutations. The genes are related to each other in that they have similar DNA sequences. One of them may account for up to 80 per cent of inherited Alzheimer's cases, while the other seems to be responsible for only a few per cent.

The two genes carry the genetic code for very similar proteins whose functions are so far unknown. However, both these human proteins have some similarities to one in a nematode worm that is involved in transporting other proteins between different parts of the cell.

The obvious first guess about the Alzheimer's proteins is that they are also involved in shuttling other proteins around, and that mutations in either gene may disrupt this function somehow and cause the disease.

Some people have tried to link the function of the new genes with APP, the protein from which beta amyloid is made. They have suggested that abnormal transport of APP within brain cells might make it linger too long in the particular part of the cell where processing to beta amyloid takes place.

The excess beta amyloid is then deposited in the brain, with disastrous effects. But this is just a first guess, and a lot more work is under way to try and found out just what the true functions of the new genes are and what goes wrong when they are mutated.

For those unfortunate families affected by familial Alzheimer's, the discovery of these new genes is very much a mixed blessing. The plus side is that it's another step along the road to eventually perhaps being able to design drugs to prevent the disease or lessen its effects. The more immediate downside is the dilemma, now so familiar to families affected by Huntington's disease, of whether family members who are at risk will want to know whether they carry a mutated form of one of these genes or not. Experience so far with Huntington's families suggests that until there is some treatment or cure, most may decide that it is best not to know.

And what does this latest discovery mean for the 90 per cent of Alzheimer's victims for whom there is no strong family history of the disease? In the last couple of years, progress has also been made in understanding this more common type of Alzheimer's, with the discovery that there is an association between Alzheimer's risk and a particular form of a blood protein called Apolipoprotein E - or Apo E for short. There are three different types of Apo E, called Apo E 2, 3, and 4.

We all inherit two Apo E genes, one from each parent. Those people who inherit either one or two copies of Apo E type 4 have a considerably increased risk of developing Alzheimer's, though it's not an all-or-nothing effect like the new familial Alzheimer's genes. Some people with no Apo E 4 genes still develop Alzheimer's, and some people who have two copies of Apo E 4, don't. Nevertheless, because Apo E 4 increases the risk for every type of Alzheimer's, early or late onset, it is a very important clue to follow up.

An obvious line of research now will be to see whether there is any functional connection between the role of Apo E and the newly-discovered proteins implicated in familial Alzheimer's. If there is, it might shed some light on the disease pathway at the molecular level.

Now that some more pieces of the jigsaw puzzle of Alzheimer's have been found, hopes have been raised that eventually it will be possible to complete the whole picture.

NORMAN SWAN: Dr Alison Stewart, talking about one of the prime challenges in medical research over the next 10 or 20 years.