A reactive intermediate generated by lipid peroxidation, 4-hydroxy-2-nonenal (HNE), has received considerable attention as a potential effector of oxidative damage and Aβ peptide-mediated neurotoxicity in Alzheimer disease (AD). However, little is known about aldo-keto oxidoreductases, a group of enzymes that constitute a major detoxifying pathway for HNE and related reactive aldehydes in human brain. We have determined the regional, cellular, and class distribution in human brain of the 4 major aldo-keto oxidoreductases that detoxify HNE: aldehyde dehydrogenase (ALDH); aldose reductase; aldehyde reductase; and alcohol dehydrogenase (ADH). Of these 4 enzymes, only ALDH and aldose reductase were expressed in cerebral cortex, hippocampus, basal ganglia, and midbrain; all 4 enzymes were present in cerebellum. In cerebrum and hippocampus, aldose reductase was localized to pyramidal neurons and mitochondrial class 2 ALDH was localized to glia and senile plaques. ALDH, but not aldose reductase, activity was significantly increased in temporal cortex from patients with AD compared to age-matched controls. These results suggest that in brain regions involved in AD, neurons and glia utilize different mechanisms to detoxify HNE, and that increased ALDH activity is a protective response of cerebral cortex to AD.