Immunocytochemical staining of hypothalamic cell groups with four antibodies to Alzheimer paired helical filaments (PHF) (i.e., anti-PHF serum 60e and monoclonal antibody (mAb) Alz-50, both directed against normal and abnormally phosphorylated tau; mAb tau-1, which recognizes tau; and mAb 3-39 to PHF, which recognizes the carboxy terminal domain of ubiquitin) revealed a clear distinction between 12 Alzheimer's disease (AD) patients and seven controls in the hypothalamus. Dystrophic neurites, which appeared to be the most specific components in AD, were most conspicuous after Alz-50 staining. However, Alz-50 also stained neuronal cytoplasm and normal, thin, beaded neurites in the paraventricular nucleus (PVN) of controls, even of young cases. This staining was clearly distinct from the staining of cytoplasm and dystrophic neurites in the PVN of Alzheimer patients. The abundant staining of dystrophic neurites and cell bodies in the nucleus tuberalis lateralis (NTL) in AD, in which no neuronal loss is observed, suggests that alterations in cytoskeletal markers do not necessarily indicate impending cell death. Moreover, the cytoskeletal changes in the NTL, sexually dimorphic and suprachiasmatic nuclei in AD indicate that this condition is not restricted to cortical areas or nuclei projecting to the cortex. Consequently, the pathophysiological implications of cytoskeletal staining in AD are at present far from clear. The human hypothalamus may not only provide a better insight into the pathogenesis of Alzheimer's disease, but could also be of help in the neuropathological diagnosis of this condition.