Brains from persons with Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI), exhibit high levels of oxidative damage, including that to phospholipids. One type of oxidative damage is lipid peroxidation, the most important index of which is protein-bound 4-hydroxy-2-trans-nonenal (HNE). This highly reactive alkenal changes the conformations and lowers the activities of brain proteins to which HNE is covalently bound. Evidence exists that suggests that lipid peroxidation is the first type of oxidative damage associated with amyloid β-peptide (Aβ), a 38-42 amino acid peptide that is highly neurotoxic and critical to the pathophysiology of AD. The Butterfield laboratory is one of, if not the, first research group to show that Aβ42 oligomers led to lipid peroxidation and to demonstrate this modification in brains of subjects with AD and MCI. The Mattson laboratory, particularly when Dr. Mattson was a faculty member at the University of Kentucky, also showed evidence for lipid peroxidation associated with Aβ peptides, mostly in in vitro systems. Consequently, there is synergy between our two laboratories. Since this special tribute issue of Aging Research Reviews is dedicated to the career of Dr. Mattson, a review of some aspects of this synergy of lipid peroxidation and its relevance to AD, as well as the role of lipid peroxidation in the progression of this dementing disorder seems germane. Accordingly, this review outlines some of the individual and/or complementary research on lipid peroxidation related to AD published from our two laboratories either separately or jointly.