Obesity is a significant risk factor for various metabolic diseases, including impaired glycemic control and hepatic steatosis. Increased body mass index (BMI) is also strongly correlated with an increased risk of dementia, particularly Alzheimer's disease (AD). AD is a progressive neurodegenerative disease, with aging being a major risk factor. Adipose tissue-derived molecules like leptin and adiponectin, along with their interaction with pro-inflammatory cytokines, impact AD progression. The interplay between obesity, impaired glycemic control, hepatic steatosis, and neurodegeneration leading to AD remains unclear, but impaired insulin signaling is a common thread. Higher insulin levels are consistently observed in AD patients compared to controls, suggesting a role for obesity and hyperinsulinemia in AD pathogenesis. These conditions also lead to lipid accumulation in liver cells, disrupting metabolic pathways and potentially accelerating AD progression. However, weight loss strategies haven't definitively reduced AD incidence, and anti-diabetic agents have shown limited success in attenuating AD. This study hypothesized that reducing adiposity, glycemic impairment, and liver fat accumulation would lessen cognitive decline. The E4orf1 protein, derived from human adenovirus type 36, was selected for investigation due to its ability to improve glucose disposal and reduce liver fat accumulation, even in the presence of insulin resistance. This proof-of-concept study utilized a transgenic mouse model expressing E4orf1 in APP/PS1 mice to test the effects of E4orf1-induced metabolic improvements on cognition under conditions of high-fat diet-induced obesity.

Existing research demonstrates a strong link between obesity, impaired glycemic control, hepatic steatosis, and the development of Alzheimer's disease. While impaired insulin signaling is a common feature, weight loss interventions have yielded inconsistent results in preventing or delaying AD onset. Similarly, the use of anti-diabetic medications has had limited success in impacting cognitive decline. Studies show a correlation between obesity, hyperinsulinemia, and the accumulation of lipids in the liver, potentially accelerating AD progression. However, the precise mechanisms by which obesity-related metabolic dysfunction contributes to AD remain elusive. This lack of conclusive evidence necessitates further investigation into the complex relationship between metabolic factors and neurodegeneration in AD.

This 20-week study employed two diet compositions: a high-fat diet supplemented with doxycycline (to induce E4orf1 expression) for 10 weeks, followed by a chow diet with doxycycline for another 10 weeks. Fourteen- to twenty-month-old male and female APP/PS1/E4orf1 (n=11) and APP/PS1 (n=7) mice were used. Body composition was assessed using EchoMRI. Glucose tolerance tests (GTT) were conducted with oral glucose gavage, measuring serum glucose and insulin levels. Hemoglobin A1c (HbA1c) was measured to assess long-term glycemic control. At the study's end, tissues (liver, adipose tissue, skeletal muscle, brain) were collected for RNA and protein analysis. Real-time quantitative PCR was used to assess gene expression. Western blotting analyzed protein abundance. Amyloid-beta (Aβ40 and Aβ42) levels were measured in brain tissue and serum using ELISA. Spatial learning and memory were evaluated using the Morris Water Maze (MWM) test. Statistical analysis used Welch's t-test to compare the two groups.

E4orf1 expression significantly improved glycemic control in older APP/PS1 mice, evidenced by lower body fat percentage (p<0.05), lower HbA1c levels (p<0.05), faster glucose clearance during GTT (p<0.001), and significantly lower endogenous insulin requirements (p<0.001). Adipose tissue in E4orf1 mice showed increased Ras and phosphoAKT expression (indicating improved insulin signaling) and increased adiponectin abundance (p<0.05). Reduced de novo lipogenesis was also observed in adipose tissue. Liver de novo lipogenesis was significantly reduced in E4orf1 mice (p<0.05) as well, suggesting protection against hepatic lipid accumulation. In the Morris Water Maze test, E4orf1 mice exhibited significantly improved escape latency (p<0.007) on trial day 4, indicating better spatial learning and memory. While there was no significant difference in hippocampal Aβ levels, serum Aβ40 levels were significantly reduced in E4orf1 mice (p<0.05). Furthermore, E4orf1 mice showed reduced expression of RAGE (advanced glycation end-products receptor) and increased neprilysin (amyloid-beta degrading enzyme) expression in the cortex, suggesting reduced Aβ production and enhanced degradation. In the hippocampus, E4orf1 increased expression of the presynaptic gene synaptophysin and the glycolytic gene fructokinase. In the cortex, E4orf1 reduced expression of the mitochondrial fission gene Fis1 and increased expression of neurogenesis genes NeuroD and DCX-1, and the glycolytic gene Enolase.

This study provides compelling evidence that improving peripheral metabolic control, specifically by reducing glycemic impairment and hepatic steatosis, can positively impact cognitive function in a mouse model of Alzheimer's disease. The observed improvements in glucose metabolism, lipid metabolism, and cognitive performance in E4orf1-expressing mice strongly suggest that E4orf1 may offer a novel therapeutic approach for addressing obesity-related cognitive decline. The reduction in hepatic steatosis, in conjunction with improved glucose homeostasis and enhanced brain functions, underscores the importance of considering the systemic metabolic impact on AD pathogenesis. While the mechanisms connecting peripheral metabolic improvements to central nervous system effects require further elucidation, the study highlights the potential for a multi-pronged approach, targeting both metabolic and neurological aspects of AD.

This study demonstrates that E4orf1 significantly improves metabolic parameters and cognitive function in an AD mouse model. The observed reduction in glycemic impairment, body fat, hepatic steatosis, and improved brain function suggests a promising therapeutic avenue for obesity-related cognitive decline. Future research should focus on elucidating the underlying mechanisms and conducting longitudinal studies with larger sample sizes to validate these findings. Pre-clinical investigations using nanoparticle-mediated E4orf1 delivery methods will be crucial for clinical translation.

This cross-sectional study used a mouse model and examined older mice (14–24 months), which might not fully replicate the human condition. The sample size, including the number of males and females, was relatively small, limiting the generalizability of the findings. The study's design did not establish causality, and further research is needed to determine the direct relationship between peripheral metabolic improvements and central nervous system changes. Finally, the findings from transgenic mouse models may not directly translate to clinical applications.