Combination anti-Aβ treatment maximizes cognitive recovery and rebalances mTOR signaling in APP mice

Drug development for Alzheimer's disease has endeavored to lower amyloid beta (A beta) by either blocking production or promoting clearance. The benefit of combining these approaches has been examined in mouse models and shown to improve pathological measures of disease over single treatment; however, the impact on cellular and cognitive functions affected by A beta has not been tested. We used a controllable APP transgenic mouse model to test whether combining genetic suppression of A beta production with passive anti-A beta immunization improved functional outcomes over either treatment alone. Compared with behavior before treatment, arresting further A beta production (but not passive immunization) was sufficient to stop further decline in spatial learning, working memory, and associative memory, whereas combination treatment reversed each of these impairments. Cognitive improvement coincided with resolution of neuritic dystrophy, restoration of synaptic density surrounding deposits, and reduction of hyperactive mammalian target of rapamycin signaling. Computational modeling corroborated by in vivo microdialysis pointed to the reduction of soluble/exchangeable A beta as the primary driver of cognitive recovery.