Fig. 4.

Exercise and a healthy diet alter the diversity of the gut microbiome, improve barrier permeability, and are associated with increased levels of SCFA-producing bacteria in humans. Therefore, a variety of human studies involving exercise, diet, and dietary supplements in older study participants have been completed or are ongoing. For example, a Mediterranean diet, involving increased consumption of nonrefined grains, fruits and vegetables, legumes, nuts, and fish, along with reduced intake of red meat and processed foods, has been associated with improved cognitive performance, reduced AD risk, and reduced gut permeability and inflammation. Another study assessing a diet characterized by increased consumption of cranberry, which is rich in polyphenols and associated with more healthy gut microbiota, documented enhanced visual episodic memory and decreased low-density lipoprotein cholesterol levels in 50- to 80-year-old people. Recognizing that it is hard for most people to alter their diet or adhere to regular exercise training, some dietary supplements have been studied in preclinical animal models consuming an unhealthy Western diet, which in humans typically involves consumption of foods high in saturated fats and simple sugars and low in fiber, and is associated with cognitive impairments and increased AD risk. For example, XN, a prenylated flavonoid found in the hop plant, Humulus lupulu, improves metabolic outcomes, including total body weight, fasting glucose, and plasma triglyceride levels, in a rodent model of obesity and metabolic syndrome. XN decreases plasma markers of reactive oxygen species and peripheral markers of dysfunctional lipid oxidation, increases uncoupled cellular respiration in obese male rats, and alters bile acid composition in mice. Dietary supplementation with XN also improves cognitive performance and affects the gut microbiome and improved cognitive performance in a mouse model of AD.