The calcium binding proteins, calmodulin and calbindin D28K, were measured by radioimmunoassay in cerebral cortex from brains with degenerative brain diseases associated with dementia. Samples were obtained from 17 normal control brains, 18 Alzheimer affected brains, and 15 brains of patients who died of a dementia process other than Alzheimer disease. Calmodulin content in the non-Alzheimer group was not significantly different from control. However, in the Alzheimer group, frontal, temporal, parietal cortex, and subjacent white matter calmodulin content was significantly reduced (66% of that found in the other 2 groups). Calmodulin extracted from temporal cortex also demonstrated reduced efficacy as an activator of 3',5' cyclic nucleotide phosphodiesterase. Calbindin D28K was reduced both in Alzheimer and non-Alzheimer dementia brains. Reduced concentrations of these important proteins may affect calcium homeostasis and the regulation of a large number of calcium mediated brain functions.