We aim to prevent Alzheimer disease (AD) in adults with DS (trisomy 21), referred to as AD in DS (AD-DS) by enhancing processing of the amyloid precursor protein (APP) to reduce the levels of the C-terminal 99 residue fragment (C99) and Aβ42. The therapeutic premise is based on: 1) increased APP gene dose is necessary for AD-DS, a finding replicated in mouse models of DS. By normalizing APP dose in DS models we eliminated: a) age-related degeneration of neurons in locus coeruleus (LCNs) and basal forebrain complex (BFCNs), b) hyper- phosphorylation of Tau, and c) enlargement of early endosomes; 2) increased C99 and Aβ42 acted via increased activation of Rab5 to induce changes in endosomes resulting in reduced trafficking of neurotrophic signals and BFCN atrophy. The evidence suggests that increased C99 and Aβ42 cause degeneration via deficits in endosomal trafficking of neurotrophic signals and motivates treatments to reduce C99 and Aβ42. Because both are substrates for γ-secretase, increasing γ-secretase activity should decrease levels and prevent or mitigate endosomal and degenerative phenotypes. BPN15606, a γ-secretase modulator (GSM), increases γ-secretase activity. In vitro, BPN15606 potently reduced C99 and Aβ42, reduced Rab5 activation and restored endosome size and trafficking of neurotrophins. In vivo, it reversed endosomal enlargement, improved LCN number, reversed Tau hyper-phosphorylation and enhanced cognition. In mouse models of AD-DS and AD/cerebral amyloidosis we will test the therapeutic hypothesis that BPN15606 will reduce the levels of C99 and Aβ42 to prevent and/or lessen neurodegeneration. The mechanistic hypothesis tested is that BPN15606 will normalize endosomal structure and function, neurotrophin signaling and trafficking, and improve cognition. Extensive pharm/tox studies qualify BPN15606 for our studies. Specific Aims: 1. To detail the time of onset of neurodegeneration in mouse models of AD-DS and AD/cerebral amyloidosis. Studies of the Dp16 model of AD-DS and Line 41 model of AD will be submitted to unbiased stereological studies of morphology and biochemistry, to quantitatively define onset of degeneration of neurons and synapses (Dp16: LCNs, BFCNs; Line 41: BFCNs, CA3), emergence of p-Tau and amyloid plaques. 2. To examine the effect of BPN15606 treatment before and after onset of neurodegeneration in the AD-DS model. Dp16 and 2N mice will be treated with an effective, safe dose of BPN15606. Guided by quantitative GO/NOGO criteria, the extent to which enhanced APP processing results in lessening of degenerative, endosomal and cognitive phenotypes will be assessed. 3. To examine the effect of BPN15606 treatment before and after onset of neurodegeneration in the AD/cerebral amyloidosis model. The same approach will guide BPN15606 studies in the Line 41 mouse. BPN15606-mediated reductions in degeneration will support the therapeutic hypothesis; normalization of endosomal and cognitive phenotypes will support the mechan...