Impact of vitamin A on the risk of mild cognitive impairment and Alzheimer's disease pathology in high‐fat‐diet–treated APP/PS1 mice

Abstract Abnormal glucose metabolism and vitamin A (VA) nutritional status promote the occurrence of cognitive impairment and Alzheimer's disease (AD). However, the effects of low VA intake, insulin resistance, and their interaction on the promoting cognitive impairment remain unclear. This population‐based study was conducted to explore the relationship between circulating VA levels with cognitive performance in T2DM subjects. Moreover, APP/PS1 mice were treated with a low VA diet to investigate the effect and mechanism of VA deficiency on glucose and Aβ metabolism in the brain. Low blood VA levels correlated with an increased risk of mild cognitive impairment in both non‐T2DM and T2DM subjects, and T2DM patients need much higher circulating VA levels to maintain normal cognitive function. High‐fat diet induced insulin resistance in APP/PS1 mice, and this impact was further enhanced by a low VA diet. A synergistic deteriorated impact of a high‐fat diet and low VA intake on AD‐like pathology was observed in APP/PS1 mice, which was demonstrated by increased cortical BACE1 expression and Aβ level and decreased IRS1 expression. Our results suggest that the nutritional status of VA is associated with cognitive performance in the elderly and synergistically enhances the pathological phenotypic changes in APP/PS1 mice treated with a high‐fat diet.