DESCRIPTION (provided by applicant): Cognitive decline due to neurodegenerative disease is emerging as one of our greatest biomedical challenges - a problem for which we have no effective medical therapies. Klotho is a longevity-promoting hormone that circulates throughout the body and brain following cleavage from its membrane form. We recently found that widespread, genetically-driven increases in klotho over the lifespan enhanced cognition in normal mice, in part through synaptic enrichment of key learning and memory molecules. In parallel with mice, we found that individuals with higher levels of systemic klotho, due to a genetic variant, showed better than average cognitive functions. We then tested whether the beneficial effect of klotho extends to neurodegenerative disease-related deficits and pathologies in mouse models. Indeed, transgenic klotho elevation enhanced cognition in mice that model aspects of both Alzheimer's (AD) and Parkinson's disease (PD). These findings are important since cognitive deficits are a key manifestation of both diseases, and even contribute to motor dysfunctions in PD. Our new data suggest that klotho confers cognitive resilience in a diseased brain, possibly through mechanisms that converge upon targets of Aβ and α-synuclein toxicity - such as at the synapse. Synapses are targeted by the pathophysiology of AD and PD, enriched by klotho, and central to neural communication and function. Thus, understanding klotho-induced structural and molecular changes to the synapse will be a convergent point in dissecting its mechanisms of resilience. We hypothesize that klotho confers cognitive resilience against deficits related to neurodegenerative disease through mechanisms of synaptic enrichment. We will pursue three aims. 1) In Aim 1, we will characterize effects of klotho on resilience to Aβ and α-synuclein 2) In Aim 2 we will explore molecular targets at the synapse that orchestrate resilience 3) In Aim 3, we will profile key associations in human disease. These studies could fundamentally advance our understanding of cognitive resilience and how klotho confers this effect against converging targets of Aβ and α-synuclein at the synapse. They could also, directly, lead to the development of urgently needed treatments for cognitive dysfunction that "boost resilience" in neurodegenerative conditions like AD and PD.