Oxidative damage is a feature of many age-related neurodegenerative diseases, including Alzheimer's disease (AD). 4-Hydroxy-2-nonenal (HNE) is a highly reactive product of the free radical-mediated lipid peroxidation of unsaturated lipids, particularly arachidonic acid, in cellular membranes. In the present study we show for the first time in brain obtained at short postmortem intervals that the levels of HNE are elevated in mild cognitive impairment (MCI) hippocampus and inferior parietal lobules compared to those of control brain. Thus, increased levels of HNE in MCI brain implicate lipid peroxidation as an early event in AD pathophysiology and also suggest that the pharmacologic intervention to prevent lipid peroxidation at the MCI stage or earlier may be a promising therapeutic strategy to delay or prevent progression to AD.