Introduction

The title of this piece is misleading - progress in unraveling the complicated role of genetics in the causation of Alzheimer's disease is so rapid that this year's information is probably already out-of-date. An article we wrote two years ago urgently needs this update. While our basic knowledge remains unchanged, it has been strengthened and extended, leading in new directions, including new approaches to prevention.

Alzheimer's disease is typically divided into early-onset and late-onset forms, with 60 to 65 years as the dividing point. Late-onset disease is far more common than the early-onset form. Mutations in four genes are clearly recognized as being associated with the development of Alzheimer's disease - three with early-onset disease, and one with late-onset disease. Mutations in all four have a common effect - an increase in the amount of abnormal fragments of a protein called beta-amyloid in the brain.

Early-onset Alzheimer's disease

Three genes have been associated with early-onset Alzheimer's disease. Mutations of one or other of these genes have been found in relatively few patients, mostly from families with two or more affected members. The abnormal genes were found in about half the early-onset patients studied.

The amyloid ß-protein precursor, or APP gene, is located on chromosome 21. A mutation in the APP gene causes an increase in the abnormal proteins called Aß-peptides. Only about 25 families worldwide have this inherited abnormality.

Two presenilin genes (PS1 and PS2) are located on chromosomes 14 and 1, respectively. Mutations in either of them are accompanied by increased formation of Aß peptides, and the occurrence of early-onset Alzheimer's.

If a close relative has early-onset Alzheimer's, it may be possible to test family members for the presence of one or more of these genes. Gene test kits have become commercially available. Their use might help in considering management of family members with suspicious symptoms, or to assist in genetic counseling. However, it is neither practical nor sensible to offer widespread genetic screening for early-onset Alzheimer's disease at present.

Late-onset Alzheimer's disease

The apolipoprotein E gene on chromosome 19 (APOE) occurs in three forms ("allele") in healthy people, but one form - the E4 allele - is more common in patients with Alzheimer's disease. Its presence seems to modify the age of onset of the disease in otherwise susceptible persons. Thus it's found most commonly in patients in their 60s, compared with those in their 70s and 80s, when the disease is, overall, more common.

Like the other three relevant genes described above, the APOE-4 allele also increases the amount of Aß-peptides deposited in the brain.

As the presence of this form of APOE isn't essential for Alzheimer's disease to occur, while its presence isn't invariably associated with Alzheimer's, testing for it isn't a particularly useful screening procedure.

The future

By April 2000, at least 40 other genes had been tested for their possible association with Alzheimer's disease. So far, none of these has been confirmed as being a focal point for mutations leading to the disease. One day, certainly, additional genes will be found to have a role in causation. At present, however, the existing four genes offer sufficient insight into the pathology of Alzheimer's disease to allow fruitful speculation on points of attack.

The steps involved in the process (greatly simplified) are as follows:

1. Mutations in the APP, PS1, PS2 or APOE genes
2. Increased production and accumulation of Aß-peptides in the brain
3. Deposition of Aß as plaques
4. An inflammatory response in the brain tissue
5. Progressive nerve cell injury
6. Free radical accumulation
7. Widespread nerve cell dysfunction and cell death, dementia

Present-day attempts to halt the disease with antioxidants (i.e. attacking point 6 above), or anti-inflammatory drugs (point 4) are clearly aiming rather late in the process.

Knowledge of the presenilin genes has led to the identification of two enzymes responsible for the formation of Aß fragments - the secretases. Development of compounds that may inhibit one or both these enzymes' activity has already resulted in a compound intended for clinical trial. This is clearly an area of hope for the future in trying to halt this devastating condition.