Neuroinflammatory mechanisms linking high‐fat diets to Alzheimer's disease vulnerability: Beyond the amyloid hypothesis

As global life expectancy increases, Alzheimer's disease (AD) incidence is rising rapidly. While research has long focused on amyloid beta (Aβ) and tau pathology, recent controversies and limited clinical success of Aβ-targeting therapies have challenged their centrality in AD. Emerging evidence highlights neuroinflammation as an earlier and potentially more critical driver of disease, particularly in response to environmental and lifestyle factors. High saturated fat diets (HFD) are strongly associated with increased AD risk in both clinical and preclinical studies. This review examines how HFD promotes AD vulnerability via neuroinflammatory mechanisms, including toll-like receptor 4 activation and complement system overactivation, which contribute to synaptic loss and cognitive decline-often independent of Aβ burden and metabolic dysfunction. Short-term HFD exposure can rapidly induce neuroinflammation and impair memory, underscoring the direct impact of diet on brain health. These insights support a shift toward targeting immune pathways and synaptic preservation in AD prevention and treatment. HIGHLIGHTS: High saturated fat diets (HFDs) increases Alzheimer's disease risk independently of obesity or insulin resistance. Neuroinflammation is a key driver of HFD-induced cognitive decline. Toll-like receptor 4 (TLR4) activation links saturated fats to synaptic loss and memory deficits. HFDs promote complement-mediated microglial synaptic engulfment. Short-term HFD exposure rapidly impairs memory and increases brain inflammation.