ABSTRACT A universal characteristic of aging animals is the dramatic decrease in their ability to respond to stress and maintain homeostasis, i.e. resilience. This is believed to be a key factor in the dramatic increase in age-related diseases and deaths observed in the elderly. This request for supplemental funding to our resilience grant entitled “Short-term measurements of physical resilience as a predictor of healthspan in mice” is designed to study the effect of age on the resilience of the brain to AD. Unfortunately, there are no studies with mice that have critically evaluated cognitive resilience in old mice comparable to the ages when AD develops in humans. Thus, the vulnerability of the brain of older mice to AD remains unexplored. We will test the following hypothesis: Decreased resilience of the aging brain results in increased susceptibility to Aβ1-42-induced cognitive decline and manipulations, such as rapamycin, that increase longevity and delay aging will improve the resilience of the brain to Aβ-induced cognitive decline. The effect of age on the resilience of the brain to Aβ will be tested by injecting Aβ1-42 directly into the brains of young and old mice. This is supported by our preliminary data demonstrating that old (24 months) male mice are more susceptible to amyloid beta (Aβ1-42)-induced cognitive deficits compared to young (6 months) mice. The following aims are proposed: Specific Aim 1: Determine whether aged mice show increased susceptibility to Aβ-induced cognitive deficits. Aβ1-42 (or peptide control) will be injected into the hippocampus of young (5-7 m), middle (15-18 m) and old (24-26 m) male and female mice. Two weeks post-injection, we will perform a battery of behavioral tests to assess cognitive resilience followed by comprehensive multi-parametric magnetic resonance imaging (MRI) to measure alterations in blood-brain barrier (BBB) permeability, neuroinflammation and metabolism in the brain. Specific Aim 2: Determine if rapamycin can improve the resilience of the brain to Aβ1-42. Studies show that rapamycin increases lifespan in mice and reduces various age-related pathologies. We will feed rapamycin (14 and 42ppm) starting at 18 months of age, and Aβ1-42 will be injected into the hippocampus at 24 months of age. Cognitive resilience will be assessed using the endpoints described in Aim 1. Rigorous analysis of these data will answer the critical question of whether pathways mediating lifespan extension increase cognitive resilience and decrease susceptibility to Aβ1-42. These experiments are critical to determine the translational potential of lifespan extending interventions in alleviating the incidence and/or progression of AD.