Protecting Progress

Over the past few years there has been tremendous progress in diagnosis and therapeutic trials on Alzheimer’s disease (AD) and related dementias. Overall, the cost/benefit relationship is shifting with success. There has been more success in disease detection and therapy and as a result, there has been a push toward increased use of imaging and other sensitive measures of AD disease severity in clinical care [1]. With the opportunities to advance diagnosis and care, there are ethical and practical concerns. We previously outlined three domains and a roadmap for ethical application of neuroimaging to AD [2]. Many of these issues were similar to ethical concerns posed by genetic risks [3] and could apply to many biomarkers or risk factors. The landscape has become far more complex as disease progression is not static and the opportunity to move toward cures involves uncertain gains for participants in research. Below we highlight three broad domains: first, early diagnosis, the second, measurement of therapeutic response, and the third, guiding decisions that restrict autonomy. Ultimately there are issues surrounding social justice and access to care that need to be considered as progress moves from research hospitals to clinics. Implementation science [4] in the context of ethical practice will be an important approach in ensuring that people face the stigma of this debilitating disease leveraging all the opportunities for progress.

The process of diagnosing AD is changing from a focus on excluding alternative etiologies to detecting positive biomarkers and symptoms. Now amyloid PET has a clinical role in differential diagnosis between frontotemporal dementia and AD. The technique also showed that vascular and AD are separable pathologies [5]. The dream of early detection has begun to come true in that we see amyloid deposition 20 years before disease onset in genetically at risk people [6], but we are still left with uncertainty since not all amyloid positive patients convert to AD. There is also a race to improve the sensitivity of cognitive measures to describe subjective cognitive impairment as an early precursor to mild cognitive impairment [7].

Rather than waiting for an answer to whether amyloid was the optimal method of diagnosing AD, research moved forward with selecting patients with amyloid pathology and targeting reduction in amyloid on PET as a measure of therapeutic response [8]. Targeting amyloid pathology in research involves a need to disclose PET results to patients who were free of symptoms since patients needed to be selected on the basis of their scans. There is now work studying best practice in this disclosure [9,10]. The courage of the investigators and patients in facing amyloid status has richly paid off. There are promising results indicating that it may be possible to reduce amyloid in the brain and that this reduction leads to stabilizing cognitive decline [11]. If the amyloid hypothesis is correct and these therapies work, there needs to be huge changes in practice to move patients into therapy rather than planning for inevitable degeneration and a reluctance to diagnose. ApoE4 genetic status increases the risk for amyloid related imaging abnormalities (ARIA), a side effect of amyloid therapy so that again, there is a need to disclose risk information and an urgent need to evaluate the emotional response to these disclosures.

Guiding Restrictions on Autonomy
With respect to the use of neuroimaging to make decisions about autonomy, we are still doubtful that imaging is the optimal approach but it can lend convergent validity. With the exception of functional MRI, most brain imaging is far removed from behavior and for the complex behaviors like driving and financial capacity that are critical for independent living, there is not sufficient data to support replacing neuropsychological evaluation. Identifying the exact time point when a patient is initially disabled is most validly determined by actually observing that behavior. That said, complex cognitive processes can be disrupted for a variety of reasons such as confusional states or stroke. If neuroimaging identifies a brain region or network that is known to correlate with the performance of critical task, that can powerfully support the validity of the measure. A wonderful example comes from Kerr et al. [12] in which they conducted a 6-year longitudinal study and cross validated a specific pattern of brain atrophy with a financial capacity instrument. More work needs to be done using this approach to validate measures relevant to autonomy.

Protecting Progress: The Costs of Paralysis and Delay
Whereas it is comforting to wait to disseminate these novel imaging and treatment opportunities, AD progresses and waiting unnecessarily raises issues of barriers of access to care and social justice that need to be considered as patients are left behind. Two thirds of patients who satisfy criteria for AD have not received a diagnosis [13]. Minorities have a particularly high rate of AD and they are less likely to be diagnosed (Alzheimer's Association Facts and Figures Report 2014 – Rural and impoverished minority elders have barriers to care [14]. And patients without study partners, often women, tend to be excluded from clinical trials. To the extent that disease-modifying treatments halt the progression of AD, if there are delays in diagnosis and treatment these populations may be left with disproportionate disability without sufficient resources.

Solutions to improve access to care may include telehealth and telemedicine. Bringing devices in the home to support and monitor could keep people in their homes longer, but there is a tradeoff with confidentiality, protection of privacy, and comfort with monitoring. Ultimately there will be a need for commercialization. In fact it is necessary for there to be collaboration with industry to move drugs to market and technologies to the community since dissemination and product testing will require vast resources. But the geriatric population in the beginning stages of cognitive decline is no longer at their peak earning potential and face vast, unfunded, care needs since facilities that cater to the early stages of disability are not supported by Medicare. This vast and increasing population of elders who face loss of driving privileges and elderly who live alone are in dire need. Clarity around ethical approaches to public-private partnerships is important as well as an appreciation for dual needs. For young companies to survive, developing a market quickly is vital and competition is fierce. For many regulatory bodies, speed is not the priority. Rules and procedures put in place to protect patients and the integrity of research rarely consider the impact on the efficiency of research. Without effective collaboration between industry and the public sector, there could be a failure or injury as industry attempts to circumvent the regulatory process or alternatively innovations will not move to market depriving patients of helpful interventions. Implementation science could provide solutions and methods to study and protect all involved.

These are a few of the ethical issues where solutions are needed but the field is vast and evolving quickly [15]. Below are additional topics. Please vote for the top three and give comments. Remember the focus of the Ethics Review Feature is to identify opportunities and solutions to ethical dilemmas ( These articles can highlight papers published elsewhere in different fields or provide novel empirical work. The goal is to protect progress by identifying risks and barriers incisively and presenting novel solutions that move progress beyond paralysis. For each patient with dementia the stakes are high as time and disease robs them of their minds.

  • Individual Patient Protections
    • Informed Consent
    • Privacy and Confidentiality
    • Protection of Rights/Care and Risk
    • Disclosure of Results (e.g., genetics and ARIA, amyloid and A4)
    • Enhancement/Prevention
    • Independence/Capacity: Driving, Housing, Finance, Medical Decisions
  • Provider/Researcher
    • Conflicts of Interest
    • Competence and Specialization
    • Placebo and novel clinical trial designs
    • Researcher/clinician independence
    • Data sharing
  • Society/Context/Justice
    • Discrimination, equity, poverty
    • Access to Therapy/Diagnosis
    • Care for Caregivers and balancing of needs and rights
  • Other

Ethics Articles Published in JAD

[1] Shulman MB, Harkins K, Green RC, Karlawish J (2013) Using AD biomarker research results for clinical care: A survey of ADNI investigators. Neurology 81, 1114-1121.
[2] Rosen AC, Bokde ALW, Pearl A, Yesavage JA (2002) Ethical, and practical issues in applying functional imaging to the clinical management of Alzheimer's disease. Brain Cogn 50, 498-519.
[3] McConnell LM, Koenig BA, Greely HT, Raffin TA (1999) Genetic testing and Alzheimer disease: recommendations of the Stanford Program in Genomics, Ethics, and Society. Genet Test 3, 3-12.
[4] Eccles MP, Mittman BS (2006) Welcome to implementation science. Implementation Sci 1, 1.
[5] Vemuri P, Weigand SD, Przybelski SA, Knopman DS, Smith GE, Trojanowski JQ, Shaw LM, DeCarli CS, Carmichael O, Bernstein MA, Aisen PS, Weiner M, Petersen RC, Jack CR, Jr. (2011) Cognitive reserve and Alzheimer's disease biomarkers are independent determinants of cognition. Brain 134, 1479-1492.
[6] Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC (2012) Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 367, 795-804.
[7] Tales A, Wilcock GK, Phillips JE, Bayer A (2014) Is there more to subjective cognitive impairment than meets the eye? A perspective. J Alzheimers Dis 41, 655-661.
[8] Sperling RA, Rentz DM, Johnson KA, Karlawish J, Donohue M, Salmon DP, Aisen P (2014) The A4 study: stopping AD before symptoms begin? Sci Transl Med 6, 228fs13.
[9] Lingler JH, Roberts JS, Schulz R, Klunk WE (2012) Development of a standardized approach to disclosing amyloid imaging results in MCI. Alzheimers Dement 8, 422.
[10] Harkins K, Sankar P, Sperling R, Grill JD, Green RC, Johnson KA, Healy M, Karlawish J (2015) Development of a process to disclose amyloid imaging results to cognitively normal older adult research participants. Alzheimers Res Ther 7, 26.
[11] Sevigny JJ, Chiao P, Williams L, Miao X, O'Gorman J (2015) Randomized, double-blind, phase 1B study of BIIB037, an anti-amyloid beta monoclonal antibody, in patients with prodromal or mild Alzheimer's disease. Neurodegener Dis 15 (Suppl 1), 311.
[12] Kerr D, Bartel T, McLaren D, Marson D (2014) Associations between brain atrophy and financial capacity in prodromal and clinical AD. Arch Clin Neuropsychol 29, 531.
[13] Boustani M, Peterson B, Hanson L, Harris R, Lohr KN (2003) Screening for dementia in primary care: a summary of the evidence for the U.S. Preventive Services Task Force 3. Ann Intern Med 138, 927-937.
[14] Roberts LW, Johnson ME, Brems C, Warner TD (2007) Ethical disparities: challenges encountered by multidisciplinary providers in fulfilling ethical standards in the care of rural and minority people. J Rural Health 23 Suppl, 89-97.
[15] Johnson RA, Karlawish J (2015) A review of ethical issues in dementia. Int Psychogeriatr, doi: 10.1017/S1041610215000848.

Last comment on 21 October 2016 by Allyson Rosen, PhD, ABPP-CN