PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD), a progressive and debilitating neurological disorder of old age, is clinically hallmarked by memory loss and neuropathologically by accumulation of Aβ plaques and neurofibrillary tangles in the brain. Synaptic dysfunction has recently emerged as another early key feature of AD; evidence suggests that synaptic density decreases up to 30% in preclinical stages of AD and correlates more closely with cognitive deficits than Aβ pathology. Although age is the single biggest risk factor for developing AD, the observation that even individuals at genetic risk for AD or harboring AD neuropathology are able to remain cognitively normal as they age has refocused research away from risk and underscored the need for investigations of the factors that confer resilience in hopes of reducing disability and disease incidence. KLOTHO is dubbed an anti-aging and longevity gene, and plays a key role in cellular metabolism, central nervous system maturation, and synaptic plasticity. Critical to this proposal is that KLOTHO also seems to enhance synaptic integrity and protects from neurodegeneration. Thus, this integrative, clinically relevant project will rigorously investigate whether KLOTHO 1) confers resilience against age- and AD-related synaptic dysfunction, and 2) modifies the relationship between such dysfunction and cognitive decline both cross-sectionally and longitudinally. The proposed study will be embedded within the robust framework of two well-characterized and longitudinally followed cohorts of ~2,000 at-risk, late-middle-aged adults (the Wisconsin Registry for Alzheimer’s Prevention [WRAP] and the Wisconsin Alzheimer’s Disease Research Center [WADRC]). All participants are already genotyped for KLOTHO and have been cognitively phenotyped for up to 20 years under WRAP/WADRC. The R01 will provide resources for a subset of these participants (N=150) to undergo multimodal biomarker assessment ([11C]UCB-J PET imaging, CSF and blood-based biomarkers) at baseline and 2-year follow-up. Completion of this study has the potential to provide invaluable insights and druggable targets for forestalling brain/cognitive deterioration with advancing age or AD pathological burden.