Research subjects face uncertainties, risks, burdens, and indignities, and research protocol requirements inhibit the physician's ability to make individualized treatment decisions. To address these problems, investigators and Institutional Review Boards (IRBs) should justify research risks using informed consent and the judgment that the risks of research are reasonable with respect to the potential benefits, if any, to subjects and to the expectation that the research will produce important knowledge. But clinical research in Alzheimer's disease (AD) presents investigators and IRBs with significant challenges to achieve these two requirements. Broadly, these challenges 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 data that begin to answer whether and how patients' cognitive impairments and the caregiving experience impact on their decision making and what kinds of research results justify research risks. We will use these data to suggest changes to the design and conduct of clinical research in AD that can meet the challenge of justifying research risks.