Therapeutic potential of a modified Mediterranean ketogenic diet in reversing the peripheral lipid signature of Alzheimer’s disease

ABSTRACT Alzheimer’s disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear. In this randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome, analyzing 784 lipid species across 47 classes. We identified substantial changes in response to intervention, notably a global elevation across all plasmanyl and plasmenyl ether lipid species among others, with many changes linked with changes to clinical and biochemical markers of AD. Leveraging our prior clinical studies on AD (n = 1,912), we found that MMKD was inversely associated with the lipidomic signature of prevalent and incident AD. Given its low risk and cost, MMKD could be a promising approach for prevention or early symptomatic treatment of AD.