MAJOR CLUES TO GENETICISTS

Few diagnoses in medicine are more dispiriting for pa-tients and their families than Alzheimer disease. This insidious dissolution of one’s most human qualities—rea-soning, abstraction, language, and memory—now affects upwards of 30 million individuals worldwide. Until re-cently, the study of Alzheimer disease was fraught with mechanistic ignorance and therapeutic nihilism. But rapid scientific progress in 3 areas, biochemical pathology, genet-ics, and animal modeling has led to an increasingly ac-cepted model of pathogenesis and the emergence of clinical trials of potentially disease-modifying agents. Alzheimer disease research has been controversial. Not surprisingly, agreement on the temporal sequence of the molecular and cellular events that lead to dementia and which steps are most amenable to intervention has been difficult to achieve. But in the last several years, substantial consensus has developed that certain biochemical changes in the hippocampus and association cortices occur many years or decades before clinical symptoms, and a rough outline of the disease cascade has emerged