INTRODUCTION: The Western diet (WD) includes ultra-processed foods rich in simple carbohydrates, salt, saturated fats, and cholesterol, but low in whole grains, fiber, and unsaturated fatty acids. Originating in the USA, it has spread globally with lifestyle changes linked to technological advancement. Alzheimer's disease (AD) appears in early-onset familial (FAD) and late-onset sporadic (SAD) forms. FAD is caused by mutations in APP, PS1, and PS2 genes, while SAD is mainly influenced by environmental and lifestyle factors.

AIM(S): Investigate the role of the liver-brain axis in AD progression by examining the effects of WD on peripheral metabolic parameters in plasma and liver, as well as amyloid-beta (Aβ) peptide deposition in the liver, followed by progressive brain amyloidosis.

METHOD(S): Transgenic Tg2576 mice (FAD model) and wild-type C57BL/6 mice (SAD risk model) were fed WD or standard diets. Metabolic parameters in blood were assessed biochemically, and liver and brain tissue were analyzed for Aβ accumulation by immunofluorescence.

RESULTS: WD rapidly induced metabolic syndrome, including hypercholesterolemia, insulin resistance, hypoglycemia, and elevated levels of liver enzymes. Even short-term exposure caused NAFLD with hepatic fat accumulation, immune infiltration and hepatocyte damage. Liver dysfunction correlated with impaired Aβ clearance by hepatocytes, resulting in Aβ buildup in liver and brain. WD accelerated Aβ deposition in Tg2576 mice and promoted age-related Aβ accumulation in C57BL/6 mice.

CONCLUSIONS: WD, via disruption of liver function, contributes to AD pathogenesis by enhancing Aβ accumulation in the brain. These findings highlight the interplay between diet, systemic metabolism, and neurodegeneration. Peripheral blood markers may serve as early indicators for AD risk and targets for prevention.

FINANCIAL SUPPORT: This study was supported by the Polish National Science Centre, project No. 2014/15/D/NZ4/04361.