Recent studies have suggested that missense mutations in the presenilin-1 gene are causally related to the majority of familial early-onset Alzheimer's disease (AD). To examine the possible involvement of presenilin-1 in late-onset sporadic AD, a quantitative analysis of its distribution in the cerebral cortex of nondemented and AD patients was performed using immunocytochemistry. Stereological analyses revealed that AD brains showed a marked neuronal loss in the CA1 field of the hippocampus and hilus of the dentate gyrus, subiculum, and entorhinal cortex. In these areas, however, the fraction of neurofibrillary tangle (NFT)-free neurons showing presenilin-1 immunoreactivity was increased compared with nondemented controls. In contrast, cortical areas, which displayed no neuronal loss, did not show any significant increase in the fraction of presenilin-1-positive neurons. Moreover, presenilin-1 immunoreactivity was reduced in NFT-containing neurons. Thus, in AD, the fraction of NFT-free neurons that contained presenilin-1 varied from 0.48 to 0.77, whereas the fraction of NFT-containing neurons that were presenilin-1 positive varied from 0.1 to 0.24. Together, these observations indicate that presenilin-1 may have a neuroprotective role and that in AD low cellular expression of this protein may be associated with increased neuronal loss and NFT formation.