The effect of dietary fat consumption on Alzheimer's disease pathogenesis in mouse models

Abstract

Alzheimer's disease (AD) is a fatal cognitive disorder with proteinaceous brain deposits, neuroinflammation, cerebrovascular dysfunction, and extensive neuronal loss over time. AD is a multifactorial disease, and lifestyle factors, including diet, are likely associated with the development of AD pathology. Since obesity and diabetes are recognized as risk factors for AD, it might be predicted that a high-fat diet (HFD) would worsen AD pathology. However, modeling HFD-induced obesity in AD animal models has yielded inconclusive results. Some studies report a deleterious effect of HFD on Aβ accumulation, neuroinflammation, and cognitive function, while others report that HFD worsens memory without affecting AD brain pathology. Moreover, several studies report no major effect of HFD on AD-related phenotypes in mice, while other studies show that HFD might, in fact, be protective. The lack of a clear association between dietary fat consumption and AD-related pathology and cognitive function in AD mouse models might be explained by experimental variations, including AD mouse model, sex and age of the animals, composition of the HFD, and timeline of HFD consumption. In this review, we summarize recent studies that aimed at elucidating the effect of HFD-induced obesity on AD-related pathology in mice and provide an overview of the factors that may have contributed to the results reported in these studies. Based on the heterogeneity of these animal model studies and given that the human population itself is quite disparate, it is likely that people will benefit most from individualized nutritional plans based on their medical history and clinical profiles.

Fig. 1. Schematic of obesity paradox, revealed in retrospective clinical studies.

A retrospective study conducted on 2 million people over 40 years-of-age showed that underweight people had the highest risk for dementia compared to individuals with a healthy weight in mid-life (a vs. b), while overweight individuals had the lowest risk for developing AD in late life (c vs. d) [17, 18]. This observation conflicts with the evidence that cardiovascular risk factors, including hypertension and type 2 diabetes, both commonly linked to obesity, strongly associate with an increased risk for developing dementia (e) [–15]. This paradox is even more complex with the reported finding that more than a 10% loss in weight within 5 years between mid- and late-life is also associated with a 50% increased risk of developing dementia (f) [18].

Fig. 2. Detrimental and protective effects of HFD consumption observed on AD-related brain pathology in AD mouse models.

The effects described throughout this review cover multiple AD mouse models and ages as well as different timelines and types of HFDs. a Markers of neuronal dysfunction: Detrimental effects of HFD consumption include increased cortical apoptosis and enhanced whole-brain oxidative stress (not neuron-specific) [34, 35]. Protective effects include increased expression of PSD-95, a marker of axonal and synaptic integrity [61]; b Aβ and tau levels: Detrimental effects of a HFD include increased Aβ plaque load and soluble Aβ in the brain [28, 29, 31, 35, 38]. Protective effects include an overall decrease in Aβ plaques [25] and tau inclusions [61]; c Microglia: Detrimental effects of HFD consumption include increased microglial activation and density [29], represented by increased expression of TREM2 and IL1β [38, 63]. Conversely, protective effects of HFD administration include decreased microglial activation, characterized by decreased CD11b expression [25]; d BBB integrity: In some mouse models, HFD consumption increases CAA (detrimental) [35], while in other models, a HFD protects the BBB as shown by decreased fibrinogen extravasation [24, 25].