Recently, there have been a number of studies indicating that there is increased oxidative damage in patients with MCI or early AD (EAD). Several of these studies have shown an increase in lipid peroxidation in MCI. The brain is subject to free radical–induced lipid peroxidation because it uses one-third of the inspired oxygen, is rich in polyunsaturated fatty acid (targets for free radical attack), and is relatively high in redox transition metal ions but is relatively low in antioxidant capacity. Lipid peroxidation causes structural changes in membranes and release of bioactive α,β-unsaturated aldehydes including 4-hydroxy-2-nonenal and acrolein. It also produces isoprostanes and neuroprostanes, which are not bioactive but serve as excellent markers for arachidonic acid and docosahexaenoic acid oxidation. One of the first studies of oxidative damage in the brain of patients with amnestic MCI demonstrated an increase in thiobarbituric acid–reactive substances (21%) and malondialdehyde (60%) (measurements of lipid peroxidation) in the temporal lobe compared with healthy controls.6 Our recent study7 showed significantly elevated mean F2-isoprostane levels in frontal, inferior parietal lobule (IPL), and occipital regions of longitudinally followed patients with MCI compared with longitudinally followed and age-matched control subjects. Mean levels in the IPL and occipital regions were higher in patients with MCI than in patients with LAD. Mean F4-neuroprostane levels were significantly higher in the IPL and occipital regions in patients with MCI compared with controls and higher than or equal to those in patients with LAD. Mean levels of both F2-isoprostane and F4-neuroprostane were higher in the hippocampus (HIP) in patients with MCI than in controls, but these did not reach statistical significance. Williams et al8 demonstrated elevated 4-hydroxy-2-nonenal levels in the HIP, superior and middle temporal gyri, and cerebellum in longitudinally followed patients with MCI compared with healthy controls. Also in this study, acrolein levels were significantly elevated in the superior and middle temporal gyri in patients with MCI; although acrolein levels were elevated in the HIP, they were not statistically significant. Comparison of patients with EAD and control subjects showed a significant increase in 4-hydroxy-2-nonenal levels in the HIP and superior and middle temporal gyri and a significant increase in acrolein levels in all of the 3 brain regions studied. All of these studies were performed on thoroughly evaluated, longitudinally followed patients with amnestic MCI and EAD and controls who had short-postmortem-interval autopsies (mean < 4 hours). These results indicate that lipid peroxidation is an early event in AD, and they also suggest that it does not increase to a much greater level with disease progression.