In response to the urgent need for effective interventions against age-related cognitive dysfunction and dementia, our research proposal addresses the pivotal challenge of delayed treatment initiation and the unexplored potential of dietary interventions. We aim to prevent pathological brain aging and associated cognitive disorders by targeting brain metabolism and increasing neuronal resilience at an early, prodromal stage of the disease. Specifically, we will conduct a double-blind, placebo-controlled trial of nicotinamide adenine dinucleotide (NAD)-replenishment therapy, utilizing the NAD-precursor nicotinamide riboside (NR), on a population with age-related frailty, who are at high risk of developing cognitive dysfunction. We will utilize the combined clinical and translational expertise of our consortium in nutrition, metabolism, the gut microbiome, and neurodegeneration, to achieve our objectives. This approach will enable us to investigate the interplay between the gut microbiome, diet, neurodegeneration, and metabolism.

The specific aims of our study include assessing the efficacy of NR treatment in alleviating physical and cognitive dysfunction associated with aging-related frailty, determining its potential in reducing the risk profile for cognitive dysfunction and dementia, and analyzing the impact of individual variability and the role of the gut microbiome in determining metabolic and clinical responses. Finally, we aim to explore the relationship between dietary factors and cognitive function in a large cohort of elderly individuals. Ultimately, this comprehensive research endeavor promises to transform our approach to dementia, offering new pathways for nutrition-based therapeutic interventions that could alter the landscape of prevention strategies for these debilitating conditions.