Our findings described herein confirm a mechanism by which ApoE4, the major genetic risk factor for sporadic AD, may decrease SirT1 and elucidate a novel mechanism for DDL-218, the active enantiomer of DDL-214, reversal of ApoE4 repression of SirT1 expression through binding to the SirT1 promoter and acting as a transcriptional ‘brake’ on SirT1 gene expression. Here, APOE is linked to Alzheimer disease.