High-Fat Diets in Animal Models of Alzheimer's Disease: How Can Eating Too Much Fat Increase Alzheimer's Disease Risk?

Abstract

High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as > 35% of fat/weight and western diets containing > 1% cholesterol or > 15% sugar. MEDLINE and Embase databases were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance have been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD.

Keywords: Alzheimer’s disease; cognition; fatty acids; high-fat diet; metabolism; neuropathology.

Fig. 1

High-fat diets (HFD) have significant metabolic effects and can contribute to Alzheimer’s disease (AD) pathology. Possible mechanisms by which HFD can modulate AD pathology are shown, whether directly in the brain or indirectly in the periphery. Data suggest that HFD may promote insulin resistance and decrease GLUT-1 and IDE at the cerebrovascular level while also triggering an inflammatory response in the brain. In the periphery, the alteration of insulin metabolism, adipokines and gut microbiota can indirectly affect brain processes. Finally, the majority of reports indicate that a prolonged exposure to a HFD increases brain Aβ levels, whether its effects in tau pathology is less clear. Aβ, amyloid peptides; BBB, blood-brain barrier; GLUT1, glucose transporter 1; IDE, insulin degrading enzyme; INSR, insulin receptor; SFA, saturated fatty acids.