A hallmark of Alzheimer’s disease (AD) is the accumulation of plaques of Ab 1–40 and 1–42 peptides, which result from the sequential cleavage of APP by the b and g-secretases. The production of Ab peptides is avoided by alternate cleavage of APP by the a and g-secretases. Here we show that production of b-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the a-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor b, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases.