The presenilin-2 (PS2) gene expression pattern in Alzheimer's disease (AD) and control brains was examined using nonradioactive in situ hybridization. Message for PS2 was primarily detectable in neurons, particularly in somal cytoplasm. Intense staining signal was most commonly found in large pyramidal neurons, whereas moderate or faint staining was usually present in smaller neurons. The pattern of PS2 gene expression exhibited a laminar distribution profile in the frontal cortex. A small subset of tangle-bearing neurons exhibited PS2 hybridization signal in AD. PS2 mRNA expression appeared correlated to a high degree with lipofuscin autofluorescence in a large subset of neurons.