A Mediterranean-style diet protects against cognitive and behavioral deficits, adiposity, and Alzheimer's disease-related markers, compared to a macronutrient-matched typical American diet in C57BL/6J mice.

Background: Research suggests that modifying risk factors may prevent or delay up to 40% of dementia cases, including Alzheimer's disease (AD). Thus, understanding the potential of healthful dietary patterns, like the Mediterranean diet (MD), in AD prevention is crucial. While supplementation of individual Mediterranean foods has demonstrated efficacy in reducing AD biomarkers and cognitive impairment in rodents, the effects of a comprehensive MD warrant further investigation. Additionally, while rodent studies often use a "Western diet" as a model for the typical American diet (TAD), these diets generally exceed the macronutrient densities of typical American consumption, particularly in fats and carbohydrates.

Objective: To better reflect human diets, we developed two diets for mice that more closely mirrored the macronutrient composition of the traditional MD or the TAD, each with matched macronutrient profiles (50% kcal from carbohydrates, 35% kcal from fat, 15% kcal from protein), and distinct food sources from Mediterranean regions or the U.S., respectively.

Methods: Male C57BL/6J mice were randomly assigned to one diet (MD or TAD) at weaning (21 days of age), which they consumed for six months.

Results: Compared to the TAD, MD animals had lower body weight, abdominal and hepatic fat, serum TNF-α, and central Aβ_1-42, while also exhibiting enhanced exploratory behavior, reduced anxiety-like behavior, and preserved spatial memory. The MD also protected against LPS-induced central inflammation and BDNF loss.

Conclusions: These findings suggest that a comprehensive MD provides protection against metabolic and AD-related markers in wildtype mice, despite matched caloric availability to the TAD.