https://creativecommons.org/licenses/by/4.0/ Background:: Vitamin A (VA) deficiency and lipid metabolism disorders are associated with the pathogenesis of Alzheimer's disease (AD). However, their effects on cortical gene expression profile and the molecular pathways related to amyloid generation remain insufficiently understood.Methods: 3-month-old APP/PS1 mice were fed with control, high fat, high fat with normal or low VA containing diets for 8 months. RNA-sequencing technique was applied to measure the cortical gene expression profile. Differentially expressed genes were further validated by real-time quantitative PCR and Western blot analysis. Additionally, SH-SY5Y neuronal cells were used to explore the functional role of the differential expressed molecule EEF1AKMT4-ECE2 (ECE2) in amyloid β (Aβ) metabolism.Results: Transcriptome analysis identified multiple differentially expressed genes related to diets containing different fat and/or VA, which are mainly involved in amyloid protein metabolism, neuronal differentiation, myelin structure, and metabolic signal transduction. Among them, Ece2 gene was identified as a key nutrient-sensitive gene, showing a significant upregulated expression under high-fat diet intervention. Hes3 and Fam168b were among the differentially expressed genes in the cortical of mice treated with diets contained different dosage of VA, and these genes potentially related to neuronal differentiation and myelin structure. In SH-SY5Y cells, Aβ treatment significantly up-regulated ECE2 protein expression. ECE2 activation rebalanced Aβ species toward Aβ40, yet its efficacy was undermined by high-fat and VA-deficient status, which triggered BACE1 over-expression, ultimately driving intracellular Aβ accumulation and extracellular Aβ40 elevation.Conclusion: High fat and low VA nutritional status significantly modified the transcriptional profile in the cortex of APP/PS1 mice. ECE2 is a nutrient-sensitive molecule involved in the regulation of cortical Aβ metabolism under high-fat and low-VA conditions. application/pdf https://gala.gre.ac.uk/id/eprint/54814/7/54814%20ZHOU_Impact_Of_High_Fat_And_Low_Vitamin_A_Intervention_%28OA%29_2026.pdf en Frontiers Media Frontiers in Nutrition Q1 Impact of high fat and low vitamin A intervention on cortical transcriptional profiles in APP/PS1 mice and neuronal EEF1AKMT4-ECE2-associated amyloid metabolism 2026-10-05 paid Ren, Xiuwen Liu, Lu Wang, Yiran Liu, Yu Wang, Xixiang Zhou, Shaobo Gong, Yunyun Wang, Yueyong Miao, Chen Wang, Ying Sun, Mengyang Yuan, Linhong QY25427 82574075 CNS-NCL2024-04 WLKFZ202603 CDSGK1202518 2026-10-22 Journal Article/Review VoR http://dx.doi.org/10.3389/fnut.2026.1923538