The theory with the largest following remains the "Amyloid Hypothesis," which assigns a central role to abnormal processing of amyloid precursor protein (APP), a protein found widely throughout the body but whose normal function remains unknown. This abnormal processing yields a fragment called beta-amyloid (Aß), which aggregates by stages into the amyloid plaques that are one hallmark Alzheimer pathology. Proponents of the amyloid hypothesis see production and aggregation of Aß as the key event in nerve cell disruption and destruction. About half of the applicants to the Alzheimer’s Association grants program propose investigations into various aspects of amyloid.

Insights into the steps involved in amyloid processing have already led to identification of two potential therapeutic approaches. One tactic relies on various strategies for stimulating an immune system response that destroys Aß. The first immunotherapeutic compound to reach clinical trials—the "Alzheimer vaccine"—failed to fulfill its early promise. Even though that trial failed, the effort may still yield valuable insights into amyloid and its role as well as point the way to refinements of the immunotherapeutic approach that may yet bear fruit.

The second amyloid-targeting strategy inhibits enzymes called secretases that cut APP into successively smaller pieces, ultimately producing Aß. Secretases are classified as proteases, the same category of enzymes targeted by the protease inhibitors that have revolutionized AIDS therapy. A number of pharmaceutical companies are developing secretases, and the first such drug has reached clinical trials.