Neprilysin is an enzyme capable of degrading beta-amyloid protein. We measured neprilysin mRNA and protein levels in brain and peripheral organs of Alzheimer disease (AD) and control cases. Neprilysin mRNA levels were lowest in the hippocampus and temporal gyrus, which are vulnerable to senile plaque development. They were highest in the caudate and peripheral organs which are resistant to senile plaque development. Levels in AD were significantly lower than controls in the hippocampus and midtemporal gyrus but not in other brain areas or peripheral organs. We also measured levels of the mRNA for the neuronal marker microtubule-associated protein-2. They were remarkably constant in all brain areas and were not lowered in AD, indicating that the neprilysin mRNA reduction in the hippocampus and temporal gyrus was not correlated with simple neuronal loss. Relative levels of neprilysin protein generally paralleled those of the mRNA. These results suggest that deficient degradation of beta-amyloid protein caused by low levels of neprilysin may contribute to AD pathogenesis.