In order to discover compounds that may be useful in the prevention of Alzheimer disease, a drug library was screened for drugs that could decrease amyloid β peptide (Aβ) accumulation secreted from a human CNS-derived cell line. Of the 2160 compounds subjected to a primary screen, 16, or 0.74%, reduced Ab accumulation by at least 40%. Seven of these compounds were confirmed to be effective in a secondary screen using each compound at a dose of 5 μM. Three of these seven compounds were more effective than the others at reducing Aβ levels in a tertiary screen, and led to 68 to 85% reductions in total Aβ, at the 25 μM dosage. The effects of these three drugs on secreted Aβ40, Aβ42, and sAPPα were also determined. Thus, we have identified lead compounds that may be useful for subsequent studies to determine the mechanism of action of each drug, as well as for pre-clinical studies to determine whether each of these drugs is safe and effective in vivo.