Genetic testing has always been controversial but,as more genes are discovered and more testsbecome available, the heat of the debatesurrounding its implementation and usage is rising.

In June, a biomedical ethics group concludedthat genetic testing for Alzheimer’s disease (AD)is inappropriate for most people. ‘Although it ispossible to test for four different genes associatedwith AD, knowing that a particular mutation ispresent does not currently benefit the patient atall,’ argues Hank Greely, Professor of Law atStanford University (Stanford, CA, USA) and co-director of Stanford’s Program in Genomics,Ethics and Society (PGES). The group, whichcomprised 38 experts in various fields includingmedicine, genetics, nursing, psychology,biomedical ethics and law, presented their fullpolicy recommendations supported by 17background papers in a special issue of the journalGenetic Testing1. But, counters Allen Roses, VicePresident and World-wide Director of Researchand Development at GlaxoWellcome, ethicaldiscussions are only a small part of the overallpicture. ‘The Stanford group initiated theircriticisms in 1996 and have taken no steps in fouryears of repeating their positions to apply for orperform any careful social studies to justify theirhypothesis,’ he says. ‘Assumed expertise withoutsupportive data is very troubling, and publishedprejudicial opinions with inadequateunderstanding of families with dementia can besterile and cruel.’

GlaxoWellcome is currently focusing oncommon genetic susceptibility to disease andRoses himself has extensive experience of treatingand counselling AD patients and their families.Although AD cases directly associated with PS1,PS2and APPare rare (Box 1), Roses maintainsthat the impact of testing of the low numbers ofaffected individuals should not be underestimated.‘For the families concerned, genetic testing shouldbe an option. Genetic counselling for similarlyrare autosomal dominant diseases is an acceptedpart of medical treatment and the dementias thatare definitely genetic in origin should be not betreated differently,’ he says. He also recommendsthat a test for the APOEallele should be availableto people with early dementia because it canincrease the accuracy of a suspected AD diagnosisfrom 60–70% to 95%. ‘If people feel strongly thatthey would like to have that certainty and aresupported in their view by responsible familymembers, we should respect that decision,’ assertsRoses, who points out that people have manysocial reasons for going ahead with the test: ‘Ifsomeone in that position needs a more accuratediagnosis to allow them to make importantdecisions for their future care, while they still can,I don’t think anyone should have the right toprevent them,’ he concludes.

Greely agrees that testing for APP, PS1or PS2could be appropriate for people in families with ahistory of early-onset AD although, given thelimited benefits, should not be viewed as medicallynecessary. However, he remains unconvinced abouttesting for APOE. ‘Testing people diagnosed withAD could increase confidence in that diagnosis forthe patient. But, and it is a very big but, a test thatrevealed that a patient was homozygous for theAPOEe4 allele would also give an indirectpredictive test for that patient’s children. Theywould discover that they definitely had one e4allele, whether they wanted to know or not, andthis raises many difficult ethical questions.’

Although the PGES group doubts the clinicalvalue of the APOEtest, they have not condemned itsuse in research. ‘Studies in which patients couldbe divided into those that carried the e4 allele andthose that did not could prove extremely useful fordrug trials,’ explains Greely. Neither has the groupruled out the possibility that testing will be moreacceptable in the future when, for example, theemergence of effective preventive therapies mightenable patients with specific mutations to delaythe onset of symptoms. Roses finds some solace inthat and stresses that ‘for those of us workingtowards treatments based on the geneticsusceptibility at the APOElocus, the first effectivetreatments cannot come soon enough.’

In addition to the medical questions raised, thefinancial implications of testing cannot be ignored.At the inaugural meeting of the UK Forum forGenetics and Insurance in late June, AngusMacdonald (Heriot-Watt University, Edinburgh, UK)of the UK’s Genetic Test and Long-Term Care StudyGroup presented findings of a study that examinedthe implications of genetic testing for AD on long-term care costs in Britain. ‘We began the study about5 years ago, at the time when arguments aboutgenetic testing were brewing in the life insurancesector,’ explains Macdonald. In the mid-1990s, someinsurers were worried about the implications ofgenetic testing and took the position that they wouldinsist potential clients disclose all information fromgenetic tests. ‘The prospect of an obligation todisclose alarmed many people in medicine, since thisraised the spectre of the AIDS test scenario wherepeople deliberately avoided the test, in case theresults were used against them at a later date,’he says.

Moves by the government stimulated proposals from the Association of British Insurersand, in 1996, the Royal Society and the Actuarial Profession became involved. ‘Until that time, everyone had assumed that if people could have genetic testing and then notdisclose the results, this would lead to adverseselection – those with poor outlooks would buy more life insurance – and companies thought this would lead to large financial losses.’ Macdonald’s early research demonstrated that, even in the worst casescenarios, this was not likely; since then, viewshave calmed.

His latest study looks at the issues involved in long-term care insurance in relation to theAPOEgene for AD. Data put into an actuarialmodel have shown that if a genetic test showedthat a person had two copies of the e4 APOEallele, their expected long-term care costs would be 10–30% higher than someone who hadtwo non-e4 alleles. ‘People with very goodpension provision might be able to absorb thesecosts, we are not sure yet; but those with poorpension provision would not. In the long term this has important implications because thedemographic changes in population will mean a greater burden on the financial and careresources of society,’ concludes Macdonald. Tom Wilkie (The Wellcome Trust, London, UK)agrees and accepts that the increased use ofgenetic testing will need to be carefullymonitored. ‘Currently it is very difficult to find out from the data available if people are being discriminated against unfairly by insurance companies on genetic grounds. The UK is setting up policies and guidelines to prevent discrimination while safeguarding thelegitimate interests of the insurers. This shouldensure that the knowledge generated by genetictests is used responsibly.’

1 McConnell, L. et al.(1999) Genetic testingand Alzheimer disease: PGESrecommendations, Genetic Testing3, 3–12

Kathryn SeniorFreelance science writer

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Genetic testing under fireBox 1. The genes associated with AD

Of the four genes associated with AD, mutations in the two presenilin genes,PS1and PS2and the APPgene, which encodes the amyloid precursor protein, are all highly penetrant and are strongly associatedwith early-onset AD. However, the relevant mutations account for only about 1–2% of all AD cases.The e4 allele of the apolipoprotein E gene (APOE) is linked with a larger proportion of AD cases(30–50%) but it has only moderate penetrance, at worst tripling the lifetime risk of developing AD.