Alzheimer’s disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) (senile plaques) and intracellular inclusions of hyperphosphorylated tau (neurofibrillary tangles). Moreover, intraneuronal Aβ plays a primary role in AD pathogenesis. A growing body of evidence suggests a link between lipid peroxidation and AD. The brain is particularly vulnerable to oxidative stress, which is responsible for the formation of highly reactive aldehydes, of which the most relevant to brain pathophysiology appears to be 4-hydroxynonenal (HNE), and cholesterol oxidation products (oxysterols). HNE production in the brain is stimulated by Aβ and, conversely, Aβ production is up-regulated by this aldehyde. Because elevated levels of HNE have been found in the brain of AD patients, it has been proposed as a biomarker of AD. Moreover, in the brain, cholesterol is primarily converted into 24-hydroxycholesterol (24-OH) which has been shown to enhance Aβ neurotoxicity in human differentiated neuroblastoma cell lines, as well as augmenting ROS generation. We observed the ability of HNE and 24-OH to potentiate Aβ cytotoxicity as determined in vitro using neuron-like cells derived from human dental-pulp progenitor cells. Cell pre-incubation with the aldehyde or the oxysterol strongly enhanced Aβ uptake and intraneuronal accumulation, by up-regulating a cluster of membrane receptors, composed by CD36, β1-integrin and CD47. Consequently, the two lipid peroxidation products markedly potentiate Aβ neurotoxicity, in terms of necrosis; this event was confirmed by the employment of specific antibodies against CD36 or β1-integrin. These data support a primary involvement of altered brain lipid metabolism in the pathogenesis of AD.