Filamentous cytoplasmic inclusions are hallmarks of Alzheimer disease (AD) and Pick disease (PD). Although previous studies show elevated zinc (Zn) in AD brain, there has been little study of zinc transporter (ZnT) proteins that are critical in the maintenance of Zn homeostasis. Using Western blot analysis, we show significantly elevated ZnT-6, the protein responsible for sequestration of Zn in the trans-Golgi network, in the hippocampus/parahippocampal gyrus (HPG) of AD subjects compared to age-matched controls and a trend toward elevated ZnT-6 in subjects with amnestic mild cognitive impairment (MCI). Based on these data, we used immunohistochemistry to investigate the cellular distribution of ZnT-6 in the HPG of control subjects and subjects with MCI, AD, and PD. Comparison of immediately adjacent serial sections stained using the modified Bielschowsky method and immunostained for ZnT-6 showed elevated ZnT-6 in 89 +/- 7% of neurofibrillary tangle (NFT)-bearing neurons in AD and 100 +/- 19% of Pick bodies in PD specimens. Confocal microscopy of HPG from MCI subjects double labeled for ZnT-6 and MC-1, a marker of early NFT formation, showed 85 +/- 4% of MC-1-positive cells were strongly ZnT-6-positive. Increased ZnT-6 immunostaining in neurons containing cytoplasmic inclusions in MCI, AD, and PD suggests a role for ZnT-6 in the pathogenesis of these lesions.