To explain the possible functional mechanism of impact of ESR1 variation on cholesterol level and Aβ in AD, even in MCI development, we suppose that along with aging, brain microenvironment of individuals carrying this ESR1 variant are much vulnerable to specific environmental factors such as altered lipids levels, thus mutant ERα which partakes in the cholesterol metabolism, would exacerbate cholesterol disturbance and triggers a series of reaction including continually Aβ production and lead to neuronal apoptosis in brain tissues, inducing MCI early and eventual AD later. This evidence concerns the gene ESR1 and Alzheimer disease.