Moderation of Aging Trajectories of Cognition and Neuropathology by Diet Composition in Middle-aged Nonhuman Primates

PROJECT SUMMARY Diet composition potently modulates trajectories of brain aging. Intake of a "Mediterranean" diet including fruit and vegetables, fish, and healthy fats is associated with reduced risk of Alzheimer's disease and related dementias including vascular dementia. Intake of a "Western" diet high in simple sugars and saturated fat is associated with increased risk of these conditions. Nonhuman primate models of diet composition effects on brain health are critical for providing insight into mechanisms of diet effects on the brain, because of challenges associated with long-term studies of diet manipulations in humans. Our previous work showed Western diet consumption (compared to Mediterranean) increased social isolation and anxiety-related behaviors, increased gray matter volume in an Alzheimer's-related temporal-parietal cortex meta-region of interest, reduced white matter volume, and resulted in lateral temporal transcriptional profiles associated with inflammation in middle- aged female cynomoglus monkeys. However, because cognitive function was not assessed in these monkeys, the interpretation of changes in biomarkers as reflecting a nascent pathological process or, alternatively, a resilient adaptation remains unclear. For example, elevated gray matter volume in monkeys consuming the Western diet may reflect impaired function associated with inflammation, or a reactive change to preserve function and promote resilience in the face of a poor diet. Furthermore, males were not studied in our previous work. To address these critical barriers to progress in the field, we propose to test the impact of Mediterranean vs. Western diet on cognitive function and translational imaging and fluid biomarkers of Alzheimer's disease risk, neuroinflammation, and neurodegeneration in middle-aged male and female cynomolgus monkeys, in a longitudinal design spanning 32 months of diet treatment, corresponding to ~9.5 human years. Our overarching hypothesis is that consumption of Western diet interacts with aging trajectories to exacerbate cognitive impairment with aging and produce pathological brain aging, whereas Mediterranean diet promotes resilient aging, preserved cognitive function, and reduction of markers of Alzheimer's disease risk, including fluid biomarkers of neurodegeneration and neuroinflammation, and PET imaging measures of microtubule stability and neuroinflammation. We expect that within and across diet treatment groups and sexes that elevated markers of neuropathology will predict cognitive decline. This project specifically examines vulnerability of middle-aged monkeys, a time in the lifespan where trajectories of aging take a turn towards successful aging or greater risk of neurodegenerative disease, with immense translational significance.