Project Summary Alzheimer’s disease (AD) is a devastating and complex neurodegenerative disorder with a crushing social and economic burden currently affecting more than 6 million patients in the US. With the number of affected individu- als projected to increase, identifying disease-modifying treatments and interventions for AD remains one of the most critical undertakings in modern biomedical research. A critical step to the development of these interven- tions involves characterizing the genes and pathways mediating AD risk and resilience. The objective of this proposal is to explore the modulation of AD genetic risk by age and examine how caloric restriction (CR), a lifespan-increasing intervention, can be harnessed to counter AD risk. The proposal will utilize state-of- the-art single-nuclei multi-omic functional genomic analyses of healthy and AD human brain tissue, as well as transgenic AD mouse models, to perform deep molecular characterization of AD risk and resilience across the genetic, epigenomic, and transcriptomic layers. Aim 1 will dissect non-coding AD genetic risk through intensive multi-omic molecular profiling of healthy and AD brains, allowing the nomination of causal variants, cell types, and pathways mediating risk. Aim 2 will identify protective mechanisms in cognitively healthy, long-lived individ- uals, including centenarians, and determine whether AD resilience manifests by maintaining a “young” state or by compensating for detrimental age-related effects and AD genetic risk. This will involve comparison across a broad age spectrum, including molecular profiles of young controls (aged 18-35) and AD patients. Aim 3 will characterize the interplay between CR and neurodegeneration in genetically diverse AD mouse models. This will provide insight into the pathways mediating lifespan-increasing interventions in the brain, their interaction with high-risk and resilient genetic backgrounds, and their overlap with AD risk and resilience pathways in hu- mans. Importantly, this proposal will directly address the connections between lifespan and AD resilience to provide a more nuanced understanding of the potential of CR and its mimetics as therapeutic strategies for AD. This proposal employs an innovative research approach combining observational and interventional study de- signs with state-of-the-art computational techniques. This approach facilitates concurrent human and mouse data analysis, expediting the discovery of molecular pathways mediating AD risk and resilience, with potential implications for developing novel AD prevention strategies. Under the mentorship of Dr. Harari and co-mentors Dr. Goate, Kaczorowski, Karch, and Lee, I will follow a rigorous training program to meet the aims of this K99/R00 award and transition into independent research leadership in the domain of AD and aging. This will include a focus on neurobiology, the biology of aging, mouse models of AD, bioinformatics, and professional development, achie...