The pathology of Alzheimer's disease (AD) involves subcortical as well as cortical structures. The authors have used immunohistochemical methods to study the molecular composition of AD plaques in the hypothalamus. In contrast to previous studies using histochemical methods, the authors observed large numbers of diffuse plaques in the AD hypothalamus labeled with an antiserum to the β-amyloid, or A4 peptide, of the β-amyloid precursor proteins (βAPPs), whereas A4-immunoreactive plaques were uncommon in the hypothalamus of patients without AD. Unlike plaques in the cortex and hippocampus of AD patients, hypothalamic plaques did not contain epitopes corresponding to other regions of the βAPPs, nor did they contain tau-, neurofilament-, or microtubule-associated protein-reactive epitopes, and did not disrupt the neuropil or produce astrogliosis. These findings demonstrate that there are substantial molecular and cellular differences in the pathologic features of AD in the hypothalamus compared with those observed in hippocampal and cortical structures, which may provide insight into the pathogenetic mechanisms of AD.