Brain aging is associated with accumulation of oxidation-induced damage, likely due to the imbalance between antioxidant defenses and intracellular generation of reactive oxygen species (ROS). Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with multiple causes, and aging is considered as the major risk factor for the development of this disease. From early stages, oxidative damage is strongly implicated in the pathophysiology of this disorder. Lipid peroxidation generates various by-products such as F2α-isoprostane, 4-hydroxynonenal, malondialdehyde, and acrolein with the latter being the most reactive. In the neuroblastoma SK-N-SH cell line, our results show that acrolein can induce cell toxicity through a nonapoptotic pathway. Moreover, acrolein can alter the redox state by depleting glutathione levels. Considering the role of oxidative stress and the toxic effect of by-products of lipid oxidation, intake of compounds with antioxidant activities such as polyphenolic compounds may be beneficial in the prevention of AD. In this chapter, we will review the role of free radical–mediated damage in AD and in transgenic mouse models and present the main intracellular target of polyphenolic compounds underlying their potential neuroprotective effect.