2011: Ethics of dementia research
The Universal Declaration on the Human Genome and Human Rights (UNESCO, 1997) is of relevance to research, treatment or diagnosis affecting an individual’s genome and covers areas such as human dignity, the rights of people concerned and the way that such treatment, diagnosis or research is carried. In the general preamble to the Declaration it is stated:
“Recognizing that research on the human genome and the resulting applications open up vast prospects for progress in improvising the health of individuals and of humankind as a whole, but emphasizing that such research should fully respect human dignity, freedom and human rights, as well as the prohibition of all forms of discrimination based on genetic characteristics.”
Two types of genetic characteristics might be identified in the course of research, namely genetic mutations and a person’s genetic susceptibility.
In an extremely limited number of families, Alzheimer’s disease is a dominant genetic disorder. It is transmissible and known as familial Alzheimer’s disease (FAD). The first gene to be identified was the amyloid precursor protein (APP) on chromosome 21 but this is limited to approximately 20 families. In most cases, the mutation occurs in the presenilin-1 gene on chromosome 14. In a very small group of families, the fault is in the presenilin-2 gene on chromosome 1 (Lovestone and Gauthier, 2001). On average, half the children of an affected parent will develop the disease. For the members of such families who develop Alzheimer’s disease, the age of onset tends to be relatively low, usually between 35 and 60. It is important to bear in mind that these genes are associated with the early onset, or familial form of the disease occurring in late middle age and that more than 90% of cases of Alzheimer’s disease occur in the 65+ age group (Eisenstein, 2011).
In 2009 and 2010, a genome-wide association study, led to the discovery of additional gene variants of CR1, CLU and PICALM, and in 2011 of the gene variant BIN 1 (all of which are believed to affect the development of late onset Alzheimer’s disease (Eisenstein, 2011; Vaughn, 2011).
There is no single gene responsible for all cases of Alzheimer’s disease. However, everyone risks developing the disease at some time and it is now known that there is a gene which can affect this risk. This gene is found on chromosome 19 and it is responsible for the production of a protein called Apolipoprotein E (ApoE). There are three main types of this protein: allele ε2, ε3 and ε4 and as every person inherits two allele, six combinations are possible. The ε4 allele, although uncommon, makes it more likely that Alzheimer’s disease will occur and at an earlier age. Just one copy would increase the likelihood fourfold, whereas two copies would lead to a tenfold increase in risk (Eisenstein, 2011). The ε2 allele, on the other hand, is believed to offer some degree of protection. However, the ε4 allele does not cause the disease, but merely increases the likelihood. For example, a person of 50, would have a 2 in 1,000 chance of developing Alzheimer’s disease instead of the usual 1 in 1,000, but might never actually develop it.
There is no way to predict whether a particular person will develop the disease. It is possible to test for the ApoE4 gene mentioned above, but such a test does not predict whether a particular person will develop Alzheimer’s disease or not. It merely indicates that s/he is at greater risk. There are in fact people who have had the ApoE4 gene, lived well into old age and never developed Alzheimer’s disease, just as there are people who did not have ApoE4, who did develop the disease.
Nevertheless, researchers may be interested in a person’s genetic status, even if this is limited to his/her susceptibility to develop dementia, as it may be affect the drug they are testing or lead to the development of more targeted and hence more effective drugs (i.e. which will be more effective for some people than others). However, whilst research into genetic status or susceptibility is of vital importance for the development of medication for dementia, the outcome of such research could have negative implications for some groups of people.
In 2001, Alzheimer Europe produced a position paper on genetic testing in which it recognised the importance of research into genetic factors linked to dementia (which might further our understanding of the cause and development of the disease and possibly contribute to future treatment). At the same time, it cautioned against the use of any genetic test for dementia unless such test was known to have a high and proven success rate either in assessing the risk of developing the disease (or not as the case may be) or in detecting the existence of it in a particular individual. Alzheimer Europe did not, at that time, consider the ethical issues linked to genetic research.
Emotional disturbance or benefit
A person who discovers by any means that s/he possesses a gene known to result in dementia may suffer emotional distress which is why genetic counselling is so important. In the case of badly conducted research, there is a risk of the person finding out about his/her genetic status “in passing” (e.g. based on allocation to a particular group or if it was used as a criterion for inclusion in a study), without there being any provisions for genetic counselling. On the other hand, for some people, genetic testing resulting in a normal result may spare people and their relatives the stress of not knowing and years of uncertainty. This would of course only apply to genetic tests which had been reliably shown to be capable of predicting future disease (please see sub-section 7.8.6 on mere susceptibility).
In most cases, genetic information is probabilistic (White, 2000). However, Leibowitz (1999) points out that people react very differently to the perceived risk of disease based on statistical probability. Whereas some people will interpret 45% probability as meaning that they are less than likely to be affected, others will treat a 3% probability as practically a diagnosis. She concludes,
“Genetic information on an individual level has the potential to change people’s lives through the infinitely powerful mechanisms of the mind. The danger lies in distortion and despair; the hope lies in a realistic understanding and appreciation of life.” (Leibowitz, 1999).
However, as people are likely to react very differently and unpredictably with regard to personal risk, one might ask whether it is justifiable to risk psychological harm in the sole interests of research.
Possible impact on relatives
In the case of forms of dementia which are genetically inherited from parents, the identification of that gene in one person could have a dramatic impact on the lives of other family members who did not necessarily receive the counselling that the person participating in the research received. There are very few families in which dementia is genetically inherited but this does not make it any less of an ethical issue. Moreover, should there be an increased interest in carrying out research on this particular group of people, the problem would occur more frequently.
In “pedigree studies”, which study the incidence and progression of a disease in families, pressure may be exerted within families on certain relatives to take part in a study which might eventually reveal unexpected information about their risk of developing that disease (White, 2000). This raises the issue of voluntariness, which is an important condition for informed consent.
Discrimination and stigmatization
An obvious risk linked to identifying a person’s genetic status or susceptibility is that they may suffer some form of discrimination if such information was disclosed to a third party (e.g. in the domain of healthcare, insurance, banking or housing). As long as a person does not know such information, s/he does not risk such discrimination (provided that confidentiality is maintained by the researchers), but once known, the person may be legally obliged to reveal it in certain circumstances and thereby suffer the consequences. This might include not being able to obtain a loan or travel insurance, or having to pay higher insurance premiums. As significant advances are made by researchers every year, it cannot be known at a particular moment in time the predictive value or implications of specific genetic information nor how society will respond to such knowledge. Even in the absence of actual discrimination, a person with a particular genetic status or susceptibility may feel stigmatized and suffer the consequences of anticipated discrimination. This could be the case not only for the person who was tested but also any of his/her relatives who are equally concerned by the results of the test.
On the other hand, Anderlik and Rothstein (2001) argue that singling out genetic information for special protection (please see sub-section on genetic exceptionalism) may actually increase the likelihood of stigma through the implication that such information must be particularly shameful.
In its position statement on genetic testing for late-onset Alzheimer’s disease, the American Geriatrics Society (2000) draws attention to the fact that very little if anything is known about the “genetic literacy” of older adults. Many left school before DNA was discovered and before prenatal genetic testing became available. They may therefore be less familiar with genetic concepts and have more difficulty grasping the issues at stake such as what they are agreeing to and the implications of having or not having access to the results of any genetic test administered in the context of research.
Genetic exceptionalism is the belief that genetic information is qualitatively different from other forms of medical or personal information. This is generally accompanied by the belief that such information should be treated differently in law (Dow, 2009) and may have implications for research. This is reflected article 4 of the International Declaration on Human Genetic Data (UNESCO, 2003).
Article 4 – Special status
(a) Human genetic data have a special status because:
(i) they can be predictive of genetic predispositions concerning individuals;
(ii) they may have a significant impact on the family, including offspring, extending over generations, and in some instances on the whole group to which the person concerned belongs;
(iii) they may contain information the significance of which is not necessarily known at the time of the collection of the biological samples;
(iv) they may have cultural significance for persons or groups.
(b) Due consideration should be given to the sensitivity of human genetic data and an appropriate level of protection for these data and biological samples should be established.
There may also be strongly held beliefs that genetic information is inherently unique and symbolically equated with the uniqueness of the individual. It’s protection may therefore be seen by some as a reflection of respect for individuals as unique members of the human species (Dow, 2009). Shah (2001) criticises such assumptions, suggesting that health and identity cannot be reduced to the sum of our genes. Moreover, health insurers typically have access to non-genetic medical information which may have predictive value (such as a history of past tuberculosis in one’s family). Legislation to protect genetic information has been described as under-inclusive and leading to inequity as it is based on the fact that whilst genetic risks transcend social class, many non-genetic risk factors (e.g. environmental factors) frequently do not (Suter, 2001).
According to Dow (2009), genetic exceptionalism may lead to a paternalistic approach to genetics and the application of the “precautionary principle” which implies that when potential adverse effects of an activity are not fully understood, such activities should not be proposed (United Nations World Charter for Nature, 1982) or should require proof of cost-effectiveness in the light of perceived threats of serious or irreversible damage. He argues that whilst there is a need to protect people, there is a risk that genetic exceptionalism might lead to regulations which deny the public the tremendous benefits that might result from research into how genetic information predicts disease and improves medical outcomes.
Anxiety about the possible implications on insurance contracts of knowing one’s genetic status may prevent people from taking part in research or lead to hostility against such research. Insurance companies may also be concerned about the possible asymmetry of information resulting in adverse selection (i.e. people with a high risk, which is unknown to the insurer, purchasing more insurance). Joly et al. (2003) point out that the restriction of access to genetic information may even be counter-productive in that life insurers are interested in covering a maximum number of applicants. Having access to genetic information might actually fuel research by the insurance industry to broaden the insurability of the general population by gaining more precise information about the link between genetic tests and mortality rate. Rather than proposing greater protection of genetic information, Joly et al. (2003) propose the use of moratoria, codes of conduct established in collaboration with the general public and transparency on the part of insurance companies.
Where the genetic information obtained is only linked to the likelihood of a person developing Alzheimer’s disease (his/her ApoE4 status), the risk of discrimination and stigmatization is still present. People carrying the allele associated with the highest risk of developing dementia may never actually develop dementia and people carrying the allele associated with the lowest risk of developing Alzheimer’s disease might develop it. As genetic susceptibility status is not a biomarker in that it cannot determine with any degree of certainty that a person will develop Alzheimer’s disease and there is as yet no cure for Alzheimer’s disease, Alzheimer Europe stated in its position of genetic testing that it was not in favour of promoting the use of such tests. We felt that the results of susceptibility testing could cause considerable distress to some people who do not fully understand their basis and limitations, particularly if the tests were to become widely available without there being adequate provisions for genetic counselling.
The right to be informed
Within the context of research, which is by definition based on uncertainty, the value of susceptibility testing may be justifiable. It may, for example, contribute towards the development of more targeted drugs. However, is it morally right for researchers to withhold information about a person’s genetic status which indicates the presence or likelihood of a medical condition? Even if the research participant never develops that condition, they might want to make certain changes in their lives based on that information (e.g. making informed decisions about their future care and treatment or delaying the possible or certain development of the condition by adapting their lifestyle habits). It is stated in article 5c of the The Universal Declaration on the Human Genome and Human Rights (1997) that each individual has the right to decide whether to be informed or not of the results of genetic examination and that the resulting consequences should be respected.
There is also the issue of transparency. Participants should be informed if researchers take genetic samples for use in any study (e.g. one which is not directly related to genetics but for which such data may be useful in comparing different sub-groups). In some cases, such information is not essential to the main study, although beneficial to the future development of drugs which are more targeted to individuals. In such cases, layered consent might be useful (White, 2000).
- Research affecting an individual’s genome shall be undertaken only after rigorous and prior assessment of the potential risk and benefits pertaining thereto.
- Genetic researchers should abide by laws pertaining to this type of research.
- Researchers should try to avoid contributing towards the coercion of relatives to take part in certain forms of genetic research.
- No genetic samples should be taken or genetic information recorded without the awareness and informed consent of the participant (or his/her legal representative).
- As genetic testing may have implications for family members, potential participants should be encouraged to involve relatives in the consent process.
- Researchers should ensure that participants fully understand explanations about genetics and genetic research, starting with the terms they use.
- No prior knowledge, even of the most basic aspects of genetics, should be assumed.
- Researchers should be careful that explanations of their findings do not mislead the general public, and lead to panic or false hopes.
- The insurance industry should be dissuaded from the inappropriate use of information about the genetics of dementia until cause and effect relationships have been scientifically established.
- The insurance industry should, in the event of emerging but inconclusive evidence of genetic or other factors affecting the development of dementia, respect a moratorium.
Last Updated: Thursday 29 March 2012