palo alto, california

Despite advances in the understanding of the genetic basis of Alzheimer's disease, genetic testing for the disease is not appropriate for most people — even for diagnostic purposes. That is the conclusion of a group of scholars, physicians, lawyers and patient advocates brought together by Stanford University's Program in Genomics, Ethics and Society.

In a draft report released last Saturday (25 October), the group points out that the value of the additional information that genetic testing provides must be balanced against the financial and psychological cost. Predictive tests should be considered in the context not only of their sensitivity and specificity, but also in relation to prospects for treatment and the non-medical risks and benefits of the test.

Only those with a clear family history of Alzheimer's disease, especially with onset before the age of 60, might be possible candidates for testing for highly penetrant mutations, such as APP, PS1 or PS2, the group says. Most individuals are unlikely to have these genes, which are estimated to cause less than 2 per cent of Alzheimer's cases.

More common is a susceptibility gene, APOE, of which one allele, E4, appears to be linked to about a 14-fold increase in risk for late-onset Alzheimer's among certain ethnic groups. About 50 per cent of all Alzheimer's cases may be attributable to E4, says Neil Risch, a professor of genetics at Stanford and co-author of a recent metanalysis. As a result, a test for APOE has much wider applicability and greater commercial potential than the other mutations.

But there is general agreement that APOE offers little predictive value — partly because there are so many causes of Alzheimer's, and not much is known about how the gene acts. Nor, according to the Stanford group, is a diagnosis confirmed by the APOE allele of clear value, especially in the light of its lack of usefulness for treatment, and its wide-ranging implications for family members who must act as surrogates for the person with dementia.

The group also pointed to the significant financial cost, which can be as high as $1,500 to $2,000, and to the potential psychological and social harm to early-stage affected individuals and relatives, who would inevitably learn of the probable nature of their own genotype.

A diagnostic test for APOE was first offered in 1993, but was withdrawn three months later after criticism. Now Athena Diagnostics offers tests for both APOE and PS1, but only for diagnostic purposes after a doctor has signed a statement that the gene donor is clinically demented.