Individuals in advanced stages of Alzheimer disease are incapable of giving or refusing legally or ethically valid consent to participation in biomedical and behavioral research protocols. Yet, many research protocols aimed at better treatment of persons with this disease can be conducted usefully only if such individuals are themselves involved as human subjects. This dilemma raises difficult issues of personal autonomy and beneficent motives. This article discusses several potential proxy decision-making mechanisms regarding research participation in light of the relevant legal and ethical concerns. The analysis is organized according to a matrix approach that takes into account procedural and substantive questions as well as the specific type of research protocol under consideration.