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The major molecular risk factor for Alzheimer disease so far identified is the amyloidogenic peptide Aβ₄₂. In addition, growing evidence suggests a role of cholesterol in Alzheimer disease pathology and Aβ generation. However, the cellular mechanism of lipid-dependent Aβ production remains unclear. Here we describe that the two enzymatic activities responsible for Aβ production, β-secretase and γ-secretase, are inhibited in parallel by cholesterol reduction. Importantly, our data indicate that cholesterol depletion within the cellular context inhibits both secretases additively and independently from each other. This is unexpected because the β-secretase β-site amyloid precursor protein cleaving enzyme and the presenilin-containing γ-secretase complex are structurally different from each other, and these enzymes are apparently located in different subcellular compartments. The parallel and additive inhibition has …