Familial Alzheimer's disease (FAD) is a rare genetic disorder that results in memory loss and cognitive deficits in midlife. Although FAD accounts for only 1-5% of all Alzheimer cases, this may be >100,000 people in the U.S. alone. Unlike its late-life counterpart, the cause of FAD is 100% genetic. Mutations in the amyloid β-protein precursor (APP) lead to alterations in the production of the amyloid β-peptide (Aβ), which characteristically deposits in the Alzheimer brain. The large majority of FAD-causing mutations (>100), however, are found in presenilin. Presenilin is the active component of γ-secretase, which cleaves APP to produce Aβ peptides. Evidence from us and others demonstrates that γ-secretase initially forms Aβ peptides of 48 or 49 amino acids in length (Aβ48, Aβ49) which are then trimmed to forms of 38-43 amino acids (Aβ38-Aβ43). Most recently, we have shown that FAD-mutant γ-secretase is dramatically deficient in this trimming activity. We propose to discover compounds that correct this biochemical defect in PS1 mutations. In this way, the imbalance between Aβ variants would be corrected, without preconceived notions about which Aβ variant is toxic to neurons. To date, no drug discovery effort specifically for FAD has been reported, and we aim to leverage our new findings for this purpose. To identify and validate compounds that correct the deficient trimming activity of FAD PS1-mutant γ-secretase complexes, the following specific aims are proposed: (1) Establish biochemical assays to test the ability of compounds to specifically increase the trimming function of FAD-mutant γ-secretase . (2) Establish cellular assays to validate the ability of compounds to specifically increase the trimming function of FAD-mutant γ-secretase complexes. (3) Test collections of analogs of γ-secretase inhibitors and modulators in the battery of established biochemical and cellular assays.