Dietary factors, neuroinflammation, plasma neurodegenerative biomarkers and Alzheimer’s disease in diverse cohorts

Project Summary N resubmission in response to PAR-22-093. Prevention strategies, such as healthy sustainable diets are critical and ase-related dementia (AD/ADRD) to have a population-wide impact on reducing the risk of AD/ADRD for the growing aging population. Healthy diets are associated with slower

cognitive decline, reduced less AD pathology, and better cognitive resilience but the underlying

mechanisms of their protective effects are unknown. These diets are rich in antioxidant nutrients, flavonoids, and essential fatty acids. Animal studies indicate the brain health benefits of these dietary factors via inflammatory and oxidative

pathways. Yet, our knowledge of how these dietary factors (diets, nutrients, and flavonoids) are related to mechanisms such as neuroinflammation and brain oxidative stress, two important aspects of AD/ADRD pathogenesis and progression in humans remains incomplete. Moreover, the diet association with emerging plasma AD and neurodegenerative biomarkers

is also not fully understood. This relationship can be studied to reflect the marker of AD pathology, degeneration, and brain-

reactive astrocytes among living persons. Disparities in AD are seen across race and sex and since relatively little is known

about diet and brain health in diverse populations, the link between diet and these biomarkers could be especially informative

in the underrepresented groups where autopsy rates are lower. The goal of this study is to examine the relationship between diet, neuroinflammation, brain oxidative stress, and plasma neurodegenerative biomarkers in a diverse population, to elucidate the link between diet and AD/ADRD. We will collect new data and leverage existing data capitalizing on four

harmonized, well-characterized, longitudinal community cohorts that enroll participants without dementia with high follow-

up rates, annual clinical evaluations, plasma collection, and brain tissue collection for those who come to autopsy. In the

first aim using autopsied brains, we will examine the relationship of diet over follow-up years with hippocampal and mid-

frontal activated microglia. Activated microglia is an early effect of neuroinflammation which enhances the risk of AD. In

the second aim, leveraging the data we assess the association of diet with oxidized lipids in the brain, which reflects oxidative

stress, another potential pathway for diet and AD. In the third aim, we examine the association of plasma phosphorylated- glial fibrillary acidic protein (GFAP) with diet in our diverse sample

and also investigate race and sex differences to inform us if group-specific dietary approaches may impact these AD/ADRD outcomes. Additionally, we examine if these plasma biomarkers are associated with activated microglia and/or oxidized

brain lipids. These data will advance the understanding of potential mechanisms linking diet with cognition and AD risk. This study will also inform designs of population-specific diet interventions and insight into personalized nutrition approaches in AD using brain health biomarkers.