Oxidative stress in Alzheimer’s disease 317 J Neural Transm (1999) 106: 317–328 The activity of the pentose phosphate pathway is increased in response to oxidative stress in Alzheimer’s disease A. M. Palmer Departments of Psychiatry and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Received July 9, 1998; accepted October 26, 1998 Summary. In order to assess the integrity of antioxidant enzymes in Alzheimer’s disease, the activities of glutathione peroxidase, glutathione reductase and two enzymes of the pentose phosphate pathway (glucose-6- phosphate dehydrogenase and 6-phosphonogluconate dehydrogenase) were determined in three regions of postmortem neocortex of controls and sub- jects with Alzheimer’s disease. The activities of glutathione peroxidase and glutathione reductase were unaffected in Alzheimer’s disease. By contrast, there was a selective increase in the activities of glucose-6-phosphate dehy- drogenase and 6-phosphonogluconate dehydrogenase in the inferior temporal cortex of Alzheimer subjects. These changes negatively correlated with the Fe 2+ /ascorbate-induced lipid peroxidation which (in a previous study of the same subjects) was also found to be selectively elevated in the inferior tempo- ral cortex. Increased activity of the pentose phosphate pathway probably occurs in response to increased prooxidant activity since both glucose- 6-phosphate and 6-phosphonogluconate inhibited H 2 O 2 -induced lipid peroxidation in a concentration dependant fashion (IC 50 = 504  105 µM and 88  12 µM, respectively). Together, these data suggest that not only is oxidative stress a feature of Alzheimer’s disease, but also that it occurs because of increased prooxidant activity rather than a diminished antioxidant capacity. Keywords: Antioxidant, dementia, free radicals, glutathione, human brain, neurodegeneration. The global impairment of higher mental function that characterise Alzheimer’s disease (AD) is, in large part, attributable to neuronal loss. Studies of AD neocortex obtained antemortem (at cerebral biopsy) indicate that not only are cholinergic, noradrenergic, serotonergic and pyramidal neurons lost early in the course of the disease (Sims et al., 1983; Neary et al.,