Abstract According to the calcium hypothesis of brain aging, disturbances of free intracellular calcium homeostasis ([Ca 2+] i) play a key role in pathology of Alzheimer's disease (AD). Recent data from neuronal tissue culture support the contribution of the β-amyloid peptide (βA) to neurodegeneration in AD, probably by disruption of the intracellular Ca 2+ regulation. On the basis of this premise, we used peripheral blood cells to examine the role of βA on Ca 2+ signalling, not only to obtain an experimental approach to investigate these effects of βA in man, but also to search for AD-specific alterations of the effects of βA on Ca 2+ signalling. This approach is based on observations indicating that the phytohemagglutinin (PHA)-induced Ca 2+ response in circulating human lymphocytes of healthy volunteers is affected by βA and its fragment 25–35 in a fashion similar to its effects on central neurons, whereas we found no effect of βA on receptor-activated Ca 2+ response in neutrophils. Therefore, we used human blood lymphocytes as peripheral model systems to search directly for AD-related abnormalities of Ca 2+ regulation, for alterations of βA effects on Ca 2+ signalling and on membrane fluidity, and for possible changes of potassium channels. In accordance with our data in neutrophils, we were unable to identify any relevant change of the PHA-induced Ca 2+ elevations in lymphocytes, which is not supporting the assumption of general alterations of cellular Ca 2+ regulation in AD. On the other hand, the amplifying effect of βA on Ca 2+ signalling was significantly reduced in lymphocytes from AD patients. Moreover, Ca 2+ responses to βA25–35 were not different between early- and late-onset AD patients. Our findings indicate that the sensitivity of the lymphocyte for the effects of βA is reduced in a high percentage of patients with probable or possible AD. As possible explanation we observed a similar reduction of the sensitivity of the lymphocyte membrane for the fluidity-decreasing properties of βA. Finally, the inhibition of the PHA-induced Ca 2+ response by tetraethylammonium (TEA) was lower in the AD group compared to aged controls. This could suggest the presence of a K + channel dysfunction on AD lymphocytes, as it has been shown on skin fibroblasts of AD patients.