Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.

Alzheimer's disease is a neurodegenerative disorder characterized by the extracellular deposition in the brain of aggregated ␤ -amyloid peptide, presumed to play a pathogenic role, and by preferential loss of neurons that express the 75-kD neurotrophin receptor (p75 NTR ). Using rat cortical neurons and NIH-3T3 cell line engineered to stably express p75 NTR , we find that the ␤ -amyloid peptide specifically binds the p75 NTR . Furthermore, 3T3 cells expressing p75 NTR , but not wild-type control cells lacking the receptor, undergo apoptosis in the presence of aggregated ␤ -amyloid. Normal neural crest-derived melanocytes that express physiologic levels of p75 NTR undergo apoptosis in the presence of aggregated ␤ -amyloid, but not in the presence of control peptide synthesized in reverse. These data imply that neuronal death in Alzheimer's disease is mediated, at least in part, by the interaction of ␤ -amyloid with p75 NTR , and suggest new targets for therapeutic intervention. ( J. Clin. Invest. 1997.

It is well established that iron, which is of considerable importance for normal neurological function, is highly regulated in all organ systems. However, until recently, iron regulation in the nervous system has received little attention. This study quantitatively compares the levels of the major iron-regulatory proteins, transferrin and ferritin, and iron itself in three cerebral cortical regions of the human brain from material collected at autopsy. Three groups were studied: 1) normal adult (under 65 yr of age), 2) aged (greater than 65), and 3) Alzheimer's disease. Normally, transferrin is more abundant in white matter than in gray matter. Ferritin is approximately 10x more abundant than transferrin throughout the brain regions examined and is evenly distributed, as is iron, in the gray and white matter. In Alzheimer's disease transferrin is consistently decreased particularly in the white matter of the various cerebral cortical regions examined whereas the iron and ferritin changes are inconsistent. The observations in this study are consistent with our general hypothesis that iron homeostasis is disrupted in the aging brain and the alterations in iron-regulatory proteins are exacerbated in Alzheimer's disease. The decrease in transferrin levels could indicate a decreased mobility and subsequent utilization of iron in the brain. Such a decrease in iron availability could play a significant role in neuronal degeneration and increased peroxidative damage known to occur in Alzheimer's disease.