Abstract Protein kinase C (PK-C) levels were determined using [ 3H]phorbol-12, 13-dibutyrate (PDB) binding and the in vitro phosphorylation of histone H I (III-S), in autopsied human frontal cortex of age- and postmortem time-matched normal and Alzheimer patients. PK-C levels in Alzheimer particulate fractions determined by both methods were about 50% of those in controls. PK-C levels in Alzheimer cytosol fractions were not significantly different from those in controls. In a parallel study, we measured the phosphorylation of a M r 86,000 protein (P86), the major protein kinase C substrate in the cytosol fraction prepared from Alzheimer frontal cortex, and found it to be reduced to 43% of that in control brains. This reduction in P86 protein phosphorylation compared to controls was not detected in brain samples prepared from demented patients without Alzheimer's disease. We considered 3 extraneous factors (postmortem delay, age and sex) which may have affected the extent of P86 phosphorylation and concluded that the reduced P86 phosphorylation in the Alzheimer samples is not due to any of them. Reduced PK-C levels and M r 86,000 protein phosphorylation may reflect a biochemical deficit related specifically to the pathogenesis of Alzheimer's disease.