IRB: Ethics & Human Research
Including Persons with Alzheimer Disease in Research on Comorbid Conditions
Alzheimer disease is a progressive neurodegenerative condition that affects 4.5 million people in the United States, with the number expected to rise dramatically over the next fifty years due to the aging of the population.1 The prevalence of Alzheimer disease is 5% in people aged 65–75, and almost 50% in people aged 85 and above. Alzheimer disease is characterized by the insidious, gradual progression of memory impairment, which leads to a decline in an individual’s cognition and ability to perform activities of daily living, changes in personality and behavior, and increased health care costs.2 There is no cure, and only a few treatments slow its progression.3 The cost for caring for people with Alzheimer disease is estimated to be $60 billion annually in the United States alone.4
Considering the disease’s prevalence and the absence of effective treatment options, it is not surprising that much research focuses on this condition. While the importance of Alzheimer disease research is recognized, there is much debate about whether Alzheimer patients should be permitted to participate in clinical trials and under what conditions. Discussions have focused on the appropriate risk-benefit ratio of Alzheimer disease trials and the types of consent (subject, proxy, or advance directive) that are acceptable.5 The debates over the ethical conduct of Alzheimer disease research centers on determining the appropriate balance between protecting a vulnerable population from the potential risks of research while allowing subjects to participate in trials that could lead to individual medical benefit, as well as medical benefit for the population as a whole.
Discussions in the literature about research on persons with Alzheimer disease have been almost exclusively concerned with studies of treatments for the disease itself.6 Although this is an important starting point, more attention should be given to the inclusion of persons with Alzheimer disease in research on comorbid medical conditions. It has been shown that the treatment of comorbid medical conditions such as cardiovascular disease, infection, pulmonary disease, renal insufficiency, arthritis, and diminution of vision and hearing can improve functionality and cognition in persons with Alzheimer disease.7 Further, characteristics of medications for the disease or even the disease itself may alter the safety or efficacy of treatments for comorbid conditions. Thus, if Alzheimer patients are underrepresented in or excluded from research on comorbid conditions, optimal and safe treatments for these conditions in this population will remain unknown. If individuals are excluded from research trials on comorbid conditions by virtue of their cognitive vulnerability, they will be protected from the risks of research, but they will also be denied the potential benefits of research participation, both individually and as a group.
This article begins with a discussion of current guidelines regarding Alzheimer disease research so as to lay a foundation for extending these guidelines to more explicitly include research on comorbid medical conditions. The article then justifies including persons with Alzheimer disease in research on comorbid medical conditions, using data from several empirical studies that show treatment of these conditions is not only beneficial to the overall health of the individual, but also may be beneficial in decreasing the symptoms of the disease. Finally, the article uses the framework of social justice as understood in the research ethics literature to examine the inclusion of historically excluded groups in research and to support the conclusion that social justice requires persons with Alzheimer disease to be included in research on comorbid medical conditions unless a robust justification for exclusion is provided.
Comorbid Medical Conditions
Because Alzheimer disease most frequently affects elderly persons, it is not surprising to find that individuals with the disease commonly suffer from comorbid medical conditions. Moreover, the increasing number of comorbid conditions has been correlated to an increasing decline in scores on the Mini-Mental State Examination (MMSE), which is used to assess mental status across five areas of cognitive function (orientation, registration, attention and calculation, recall, and language).8 In the clinical setting, treatment of comorbid conditions has been shown to improve the quality of life for Alzheimer patients and even to decrease the clinical manifestations of the disease itself.9 Thus, the standard of clinical care for Alzheimer disease includes diagnosis and treatment of comorbid medical conditions.
Many studies have been done to determine the prevalence of comorbid conditions in individuals with Alzheimer disease. Patients hospitalized with Alzheimer disease have an average of 7.97 comorbid conditions, commonly including femur fracture, cardiovascular disease, diabetes, and musculoskeletal and genitourinary disorders.10 Several neuropsychiatric comorbidities also affect persons with Alzheimer disease, with apathy, depression, and anxiety being the most common.11 Not only do comorbid conditions affect the quality of life of individuals with Alzheimer disease, they also can affect the quality of life of their caregivers.12 Further, comorbid conditions are not only more common in individuals with Alzheimer disease when compared with age-matched controls,13 they are also more costly when compared with those controls. Diabetes and congestive heart failure are the most prevalent and costly comorbidities in persons with Alzheimer disease.14 The bulk of these higher costs results from Alzheimer patients using inpatient and skilled nursing facilities, reflecting both more hospital admissions and longer stays.15
Comorbid medical conditions also contribute significantly to mortality in individuals with Alzheimer disease. Congestive heart failure, ischemic heart disease, and diabetes present at diagnosis of Alzheimer disease are positive predictors of mortality.16 Further, cardiovascular disease and pneumonia are both more common proximate causes of death in patients with Alzheimer disease than dementia itself.17 Thus, comorbid conditions are not only prevalent and costly, but they also contribute significantly to mortality in individuals with Alzheimer disease. The management of comorbid medical conditions is a central element in the appropriate care of patients with Alzheimer disease, and research that tests the efficacy of new experimental treatments for these conditions has the potential to provide direct benefits to individual participants.
As Kipnis notes, persons with Alzheimer disease have a “cognitive vulnerability” because they may not have the ability to fully participate in the informed consent process or to decide to withdraw from a study in which they are enrolled.18 Informed consent is a central criterion for ethical research.19 The four basic elements for fully informed consent are disclosure, understanding, competence, and voluntariness.20 Alzheimer disease can diminish an individual’s ability to understand what is being disclosed in the informed consent process and to make and communicate a voluntary decision regarding research participation. When a potential research subject is unable to provide consent due to diminished decisional capacity, special protections may be warranted.21 In these situations, it is important to determine if the person’s cognitive vulnerability limits autonomy to the extent that she cannot participate in the informed consent process or needs special accommodations to participate. Because Alzheimer disease causes progressive neurodegeneration, individuals at the early stages of disease may show little to no deficit in cognitive function, while those with advanced disease may exhibit an almost complete lack of cognition. Guidelines for research on individuals with Alzheimer disease should recognize the spectrum of cognitive vulnerability in individuals with this disease and provide appropriate safeguards for persons with diminished decision-making capacity without restricting access to research participation for those who are capable of making a decision about whether to participate.
Federal regulations governing research with humans do not provide specific guidance for research involving persons with diminished decision-making capacity.22 However, two professional organizations (the Alzheimer’s Association23 and the American Geriatric Society24 ) and one national advisory commission (the National Bioethics Advisory Commission, or NBAC25 ) have developed specific guidance for such research.
The guidelines developed by these organizations generally recognize two considerations in studies involving persons with dementia and other cognitive disorders: impaired decision-making capacity and the potential risks and benefits of the research. NBACguidelines, which are the most comprehensive, identify three general categories of decision-making capacity relevant to research involving persons with Alzheimer disease: 1) decision-making capacity is intact, 2) decision-making capacity is intact when the study begins but cognitive deficits limit decision-making capacity during the study, and 3) decision-making capacity is not intact when the study begins.
NBAC’s first category is only applicable to short-term studies because the unpredictable nature of Alzheimer disease will not allow researchers to know if subjects will maintain decision-making capacity throughout a long-term study. Because Alzheimer disease is degenerative, declines in cognitive abilities should be expected in studies that span longer periods of time. NBAC recommends that researchers take steps in anticipation of cognitive decline to ensure that participants are adequately protected throughout the duration of the study. Protective measures include obtaining research advance directives from participants and urging them to appoint a legally authorized representative (LAR) to make research decisions for them. Ideally, persons who do not have decision-making capacity at the informed consent stage would have a research advance directive or an LAR to make research decisions, though these practices are uncommon.26
NBAC recognizes three general categories of research involving persons with Alzheimer disease with respect to risks and benefits: minimal risk research; research that presents greater-than-minimal risk, but reasonable potential for direct benefit; and research that presents greater-than-minimal risk with no reasonable potential for direct benefit.27 According to NBAC, persons with cognitive conditions like Alzheimer disease should be permitted to participate in research involving greater-than-minimal risk that has reasonable potential for direct individual benefit if 1) the person can give informed consent, 2) the person has given prospective authorization for research participation with an advance directive, or 3) the LAR gives permission. These guidelines recognize that it may be in the best interests of individuals with impaired decision-making capacity to participate in greater-than-minimal risk research that also presents the prospect of direct benefit.
The American Geriatric Society goes further than NBAC in asserting that “research on demented subjects to study conditions other than dementia itself can be justified.”28 This position recognizes that there may be legitimate reasons for including persons with Alzheimer disease in research on other health-related conditions (e.g., improving the treatment of these conditions in individuals with Alzheimer disease, ameliorating the effects of Alzheimer disease, and identifying treatments that are safe and effective for this population). If persons with Alzheimer disease are commonly affected by comorbid medical conditions for which new treatments are being developed through research, then participation in these studies offers the prospect of direct health benefit. If this is the case, it can be argued that research on comorbid medical conditions that has the potential to provide direct benefit meets the requirements of NBAC’s second category of research (i.e., research that poses greater-than-minimal risk but offers the prospect of direct benefit). Thus, when those conditions are met, persons with Alzheimer disease should be allowed and encouraged to participate in this research, within the confines of the safeguards that are already in place regarding the consent process.
Some commentators disagree with broadening the interpretation of direct benefit in Alzheimer disease research to include any health benefit. Rather, they argue for a narrow interpretation of direct benefit in which potential benefit must be directly related to the disease itself as a way to ensure that persons with diminished decision-making capacity are not unfairly burdened by involvement in research.29 The Alzheimer’s Association statement that “the involvement of people with dementia [is allowed] on grounds that such individuals are the only appropriate research subjects for answering the question”30 appears to reflect this view. From this perspective, persons with Alzheimer disease would be excluded from most research on conditions other than Alzheimer disease—such as cardiovascular disease, diabetes, and depression—unless the studies focused specifically on those conditions in persons with Alzheimer disease. This is because Alzheimer patients would not be the only appropriate research subjects. While this stance protects persons with Alzheimer disease from the risks of research participation, it also denies these individuals and the population of Alzheimer patients as a whole the potential benefits of participation in these studies.31
Social Justice and Research Participation
The Belmont Report states that “an injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly.”32 Unfair selection of research participants is the manifestation of injustice in research and can occur in two ways: prohibiting research participation without justification or unjustifiably overincluding certain categories of participants, leading to undue burden for that population. In the wake of significant abuses of vulnerable persons in research, protection has sometimes been operationalized as nonparticipation.33 Thus, one way to protect vulnerable groups from the risks and burdens of research participation is to categorically deny them the opportunity to participate. However, this approach could be interpreted as unfair subject selection. Excluding some entire categories of individuals from research denies them the opportunity to obtain potentially beneficial treatments available only within clinical trials and excludes information about their participation from the generalizable knowledge that the research generates.34
The tension between protecting vulnerable populations by excluding them from research and allowing them to have the opportunity to receive potential benefits from research participation is not unique to persons with Alzheimer disease. For instance, the justice framework developed in the Belmont Report has been used to argue that historically excluded groups, most notably women, must be included in research. Advocates for the participation of women in research have argued that social justice requires that women be given the opportunity to share in the benefits of research participation for several reasons. There is scientific evidence that males and females manifest some diseases and respond to some treatments in significantly different ways.35 If women are not allowed to participate in studies designed to yield generalizable knowledge, then the results of research studies may not be applicable to them. Without this knowledge, women could be exposed to ineffective treatments and unexpected side effects when the treatments are used clinically, and the exclusion of women could limit or delay the development of effective treatments specific to them.36 Further, because some promising interventions are available only within clinical trials, excluding women from these trials denies individuals in this group access to promising interventions.37
Failure to include persons with Alzheimer disease in research on comorbidities common in this group raises similar justice concerns, and these concerns over justice should shape our evaluation of whether to include persons with Alzheimer disease in research on common comorbidities. There are several ways in which individual research subjects with Alzheimer disease could potentially benefit from participation in research on comorbid medical conditions. First, they would have access to potential benefits of research participation in general (e.g., close monitoring of disease progression) and access to promising new therapies. Further, because treating comorbidities can actually improve the symptoms and progression of Alzheimer disease, research participants with the disease may also derive direct benefit from the study with respect to Alzheimer disease itself.
The entire population of persons with Alzheimer disease also has the potential to benefit from participation in studies on comorbid conditions for several reasons. First, persons with Alzheimer disease are usually on specific medications for the disease that could impede or enhance the efficacy and/or the metabolism of treatments for comorbid conditions. By including this population in their studies, researchers could discover trends relating to drug interactions, efficacy, and side effects affecting Alzheimer disease participants. However, many research studies require the discontinuation of medications in order to participate, so the use of Alzheimer disease medications could be a legitimate justification for excluding Alzheimer disease patients from trials on comorbidities.
Second, because the pathophysiology of Alzheimer disease is not fully understood, the disease itself may have an impact on treatments for comorbid medical conditions, and by including subjects with Alzheimer disease in studies of these conditions, researchers could uncover trends relating to drug efficacy or side effects influenced by the disease itself. There are not only potential benefits to including persons with Alzheimer disease in research on comorbidities with respect to the population, but also potential harms to excluding them. If researchers fail to include persons with Alzheimer disease in research on comorbid medical conditions, this population will be at risk of being exposed to treatments that are ineffective or that interfere with the treatments for Alzheimer disease once investigational agents are approved for use in the clinical setting. If this occurs, the population of persons with Alzheimer disease will be at a disadvantage because the lack of knowledge about effective treatments could delay appropriate control of comorbidities and, in turn, contribute to faster progression of Alzheimer disease.
The inclusion of individuals with Alzheimer disease in research studies on comorbid conditions is also required for scientifically valid trial design. Phase III and IV clinical trials are designed to include a sample of individuals that is representative of the population who might use the experimental treatment. Considering that the prevalence of Alzheimer disease is 5% in persons 65–75, and close to 50% in persons over 85, individuals with the disease constitute a significant proportion of the elderly population.38 Therefore, if a study involves a medication likely to be used by the elderly because it is intended to treat a condition common to this population, researchers should recognize that a significant proportion of the target population will have Alzheimer disease, and persons with the disease should be included in the trial in order to study a representative sample of the population. Thus, both the framework of social justice and scientific validity justify the inclusion of individuals with Alzheimer disease in research on comorbid medical conditions.
The dialogue about research on persons with Alzheimer disease should be extended to include clinical trials involving common comorbid medical conditions. Including persons with Alzheimer disease in some of these clinical trials can be justified when the trials offer the prospect of direct benefit, even if the research poses more than minimal risk. Further, the concept of social justice in research that calls for equality of opportunity to receive both the individual and population benefits of research participation supports the inclusion of individuals with Alzheimer disease in research on comorbid medical conditions common to this population. Thus, the inclusion of persons with Alzheimer disease in research on comorbid conditions is not only justified, but should be required. As NBAC and others have noted, measures can be taken to protect the rights and interests of persons with Alzheimer disease without having to exclude them from potentially beneficial research.
I would like to thank Ana Iltis for providing guidance throughout the development of this paper.
Anji Wall is an MD/PhD student at the Center for Health Care Ethics, Saint Louis University, Saint Louis, MO.
1. Grossman H, Bergmann C, Parker S. Dementia: A brief review.Mount Sinai Journal of Medicine2006;73(7):985-992.
2. Desai AK, Grossberg GT. Diagnosis and treatment of Alzheimer’s disease.Neurology2005;64(12 Suppl 3):S34-39.
3. See ref. 1, Grossman et al. 2006.
4. Cummings JL et al. Guidelines for managing Alzheimer’s disease part I: Assessment.American Family Physician2002;65(11):2263-2272.
5. Dresser R. Research involving persons with mental disabilities: A review of policy issues and proposals. In: National Bioethics Advisory Commission.Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity. Volume II: Commissioned Papers, 1998; Moreno JD. Critical issues concerning research involving decisionally impaired persons. In: National Bioethics Advisory Commission.Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity. Volume II: Commissioned Papers, 1998; Post SG. Why the tolerance of potential harms? Research ethics in Alzheimer disease.Accountability in Research1999;7(2-4):241-253; Post SG. Full-spectrum proxy consent for research participation when persons with Alzheimer disease lose decisional capacities: Research ethics and the common good.Alzheimer Disease and Associated Disorders2003;17 Suppl 1:S3-11.
6. See ref. 5, Post 2003; Karlawish JH et al. Informed consent for Alzheimer’s disease clinical trials: A survey of clinical investigators.IRB: Ethics & Human Research2002;24(5):1-5; Stocking CB et al. Ethics reporting in publications about research with Alzheimer’s disease patients.Journal of the American Geriatric Society2004;52(2):305-310; Stocking CB et al. Are the rules for research with subjects with dementia changing? Views from the field.Neurology2003;61(12):1649-1651.
7. See ref. 2, Desai and Grossberg 2005; See ref. 4, Cummings et al. 2002.
8. Backman L et al. Rate of cognitive decline in preclinical Alzheimer’s disease: The role of comorbidity.Journals of Gerontology Series B: Psychological Sciences and Social Sciences2003;58(4):P228-236.
9. See ref. 2, Desai and Grossberg 2005; See ref. 4, Cummings et al. 2002.
10. Zamrini E et al. Medical comorbidity in black and white patients with Alzheimer’s disease.Southern Medical Journal2004;97(1):2-6; Doraiswamy PM et al. Prevalence and impact of medical comorbidity in Alzheimer’s disease.Journal of Gerontology Series A: Biological Sciences and Medical Sciences2002;57(3):M173-177; Sanderson M et al. Comorbidity associated with dementia.American Journal of Alzheimers Disease and Other Dementias2002;17(2):73-78.
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12. Moretti R et al. Depression and Alzheimer’s disease: Symptom or comorbidity?American Journal of Alzheimers Disease and Other Dementias2002;17(6):338-344.
13. Hill JW et al. Alzheimer’s disease and related dementias increase costs of comorbidities in managed Medicare.Neurology2002;58(1):62-70; Fillit H, Hill JW, Futterman R. Health care utilization and costs of Alzheimer’s disease: The role of comorbid conditions, disease stage, and pharmacotherapy.Family Medicine2002;34(7):528-535; Allan LM et al. Prevalence and severity of gait disorders in Alzheimer’s and non-Alzheimer’s dementias.Journal of the American Geriatric Society2005;53(10):1681-1687.
14. See ref. 13, Hill et al. 2002.
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16. Larson EB et al. Survival after initial diagnosis of Alzheimer disease.Annals of Internal Medicine2004;140(7):501-509.
17. Tschanz JT et al. Dementia: The leading predictor of death in a defined elderly population: The Cache County Study.Neurology2004;62(7):1156-1162.
18. Kipnis K. Vulnerability in research subjects: A bioethical taxonomy. In: National Bioethics Advisory Commission.Ethical and Policy Issues in Research Involving Human Participants. Volume II: Commissioned Papers and Staff Analysis, 2001.
19. The Nuremberg Code. https://ohsr.od.nih.gov/guidelines/nuremberg.html; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC: Government Printing Office, 1979.
20. Berg JW, Appelbaum PS.Informed Consent: Legal Theory and Clinical Practice. 2nd ed. Oxford, U.K.: Oxford University Press, 2001.
21. See ref. 19, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979.
22. Department of Health and Human Services. Protection of Human Subjects. 45 CFR 46; Food and Drug Administration. Protection of Human Subjects. 21 CFR 50.
23. The Alzheimer’s Association.Ethical Issues in Dementia Research, 2007. https://www.alz.org/national/documents/statements_
24. Sachs GA.American Geriatrics Society Position Statement Informed Consent for Research on Human Subjects with Dementia, 2007.
25. National Bioethics Advisory Commission.Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity. Volume I, 1998. More recently, the Secretary’s Advisory Committee for Human Research Protections has been investigating whether the Department of Health and Human Services should issue guidance and/or additional regulations for research involving individuals with impaired decision-making capacity. See the Subcommittee on Inclusion of Individuals with Impaired Decision-Making in Research (SIIIDR), https://www.hhs.gov/ohrp/sachrp/
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27. See ref. 25, The National Bioethics Advisory Commission 1998.
28. See ref. 24, Sachs 2007.
29. See ref. 5, Moreno 1998.
30. See ref. 23, The Alzheimer’s Association 2007.
31. See ref. 5, Post 1999.
32. See ref. 19, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979.
33. List JM. Histories of mistrust and protectionism: Disadvantaged minority groups and human-subject research policies.The American Journal of Bioethics2005;5(1):53-56; author reply W15-8.
34. See ref. 33, List 2005.
35. See ref. 33, List 2005.
36. Weijer C. Selecting subjects for participation in clinical research: One sphere of justice.Journal of Medical Ethics1999;25(1):31-36.
37. Brody BA.The Ethics of Biomedical Research: An International Perspective. New York: Oxford University Press, 1998.
38. See ref. 2, Desai and Grossberg 2005.
Anji Wall, “Including Persons with Alzheimer Disease in Research on Comorbid Conditions,”IRB: Ethics & Human Research31, no. 1 (2009): 1-6.