Genetic modifiers of the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) response

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ABSTRACT Excess iron (Fe) deposition has been implicated in Alzheimer's disease (AD). Adherence to the Mediterranean- DASH Diet Intervention for Neurodegenerative Delay (MIND) dietary pattern may reduce the rate of cognitive decline and risk of AD. MIND is also relatively low in dietary Fe and rich in antioxidant and Fe-chelating phytonutrients that, in turn, may protect against Fe-induced neurotoxicity. Dietary Fe poorly correlates with biological levels partly due to diet measurement error, compensatory mechanisms, health status and genetic factors. Genetic factors can serve as tools to understand mechanisms underlying the relationship between MIND and AD and who especially benefit when adhering to this diet. Genome-wide association studies have identified loci correlated with peripheral Fe that only partly overlap with those identified for brain quantitative susceptibility mapping (QSM)-Fe; consistent with unique regulation of systemic and brain Fe. Whether these loci associate with directly measured postmortem brain Fe is unclear. R01AG065398 leverages the first MIND trial as well as existing community- and population-based data, to examine how genetic differences in AD predisposition and select nutrient metabolism modify the response to MIND. This Supplement extends this R01 to Fe and will be the first to i) investigate the genetic architecture of peripheral Fe, brain QSM-Fe and postmortem brain Fe and ii) test the hypothesis that participants with genetically inferred Fe dysregulation benefit the most when adhering to MIND compared to participants with lower susceptibility profiles. Our research will provide mechanistic insights into the role that MIND may play in slowing cognitive decline attributed to Fe and will also inform the implementation of MIND for optimal effectiveness.