Choline and Cognitive Health: Evaluating the Impact of Choline on Cognitive Decline and Alzheimer’s Disease Biomarkers - Alzheimer’s disease (AD) cases are on the rise in the USA, with a particularly high incidence in Arizona (AZ), emphasizing an urgent need to identify contributing factors. Elder adults living in rural communities face significantly higher risks of cognitive decline and AD, yet these communities are drastically understudied due to geographic isolation and limited access to research infrastructure. Rural communities exhibit high rates of obesity and type 2 diabetes (T2D), metabolic disorders that are significant risk factors for AD. Identifying contributing risk factors is necessary to understand the high prevalence of AD. Recent evidence indicates that the dietary nutrient choline is essential for preventing widespread organ damage, obesity, glucose metabolism impairments, cognitive decline, and AD pathology. While choline is produced endogenously by mammals, amounts fail to meet bodily demands, requiring dietary consumption. Established adequate intake of dietary choline per day for adults (♀= 425mg, ♂= 550mg) is not reached by a large portion of the population. Such deficiencies are more prevalent in certain socioeconomic groups, which are less investigated in rural communities. Choline, found in eggs, organ meats, fish, fruits, and vegetables, provides methyl donors for gene regulation, supports cell membrane structure through fat synthesis, and serves as a precursor to acetylcholine, essential for memory and muscle control. Choline intake also reduces systemic inflammation and can lower levels of homocysteine (hcy), a harmful amino acid that promotes inflammation and is elevated in individuals with obesity, T2D, and AD. Elevated hcy has also been shown to contribute to amyloidosis and tau pathogenesis by increasing kinases that increase amyloidogenic cleavage of the amyloid precursor protein (APP), γ-secretase, and glycogen synthase kinase 3β (GSK-3β) and cyclin dependent kinase 5 (CDK5) that hyperphosphorylate tau. Whether (1) low dietary choline intake and low circulating choline levels contribute to the high rates of metabolic dysfunction, cognitive decline, and AD risk in rural communities, and (2) whether choline intake at estimated human deficiency levels impact metabolic and AD-like pathogenesis, while supplementation ameliorates such effects, remains unexplored. Aim 1 will assess the impact of dietary choline intake and circulating choline levels on metabolic and neurocognitive health in participants from six rural and four urban cities throughout AZ using our newly deployed MindCrowd mobile Lab, a mobile trailer that combines cognitive testing, blood-based biomarker profiling, and ultra-low field brain imaging MRI technology, facilitating aging research in understudied groups, such as those in rural zip codes. Aim 2 will assess the impact of varying dietary choline intake levels on hcy, neuroinflammation, AD-like pathogenesis and associated behavioral deficits in the 3xTg-AD mouse model of AD, validating blood biomarker changes to those identified in human participants. The proposed work will have broad implications for understudied rural communities and those with high risk for cognitive aging and AD, offering a potential preventative strategy through simple dietary changes to offset incidence of metabolic and neurological disease.
