We provided multiple lines of evidence to show that overexpression of ACAA1 p.N299S in APP/PS1ΔE9 mice significantly aggravated Aβ pathologies and Aβ-mediated neurodegeneration, supporting ACAA1 as a sensitizing factor for Aβ pathology and as a novel mechanism underlying the AD risk. This evidence concerns the gene ACAA1 and Alzheimer disease.