Background: Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of beta-amyloid peptides (A beta), and could thus contribute to the onset of AD. Methods: We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor beta (RAR beta) and Retinoid X Receptor gamma (RXR gamma) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20). Results: The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal A beta(40) and A beta(42), as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal A beta load. However, the expression of Rxr-beta in the hippocampus was negatively correlated with the amount of both soluble and insoluble A beta in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RAR beta levels. However, it evidenced a switch from a 60-kDa-RXR gamma to a 55-kDa-RXR gamma in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. Conclusion: Our data suggest that (i) an altered expression of RXRs receptors is a contributor to beta-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females.