Addressing the ethical challenges of clinical trials that involve patientswith dementia

Research subjects face uncertainties, risks, burdens, and indignities, and research protocol requirements inhibit the physician's ability to make indi vidualized treatment decisions. To address these problems, investigators an d Institutional Review Boards (IRBs) should justify research risks using in formed consent and the judgment that the risks of research are reasonable w ith respect to the potential benefits, if any, to subjects and to the expec tation that the research will produce important knowledge. But clinical res earch in Alzheimer's disease (AD) presents investigators and IRBs with sign ificant challenges to achieve these two requirements. Broadly, these challe nges are the result of the impact of patients' cognitive impairment and the caregiving experience on decision making and the indeterminacy of defining clinically meaningful treatment benefits. In this article, we review the d ata that begin to answer whether and how patients' cognitive impairments an d the caregiving experience impact on their decision making and what kinds of research results justify research risks. We will use these data to sugge st changes to the design and conduct of clinical research in AD that can me et the challenge of justifying research risks.