Obesity triggers chronic systemic inflammation that compromises the blood-brain barrier and primes brain microglia toward pro-inflammatory states, while simultaneously disrupting gut microbiota composition and increasing intestinal permeability. This dual mechanism creates a feedback loop where altered microbial metabolites and endotoxins further amplify neuroinflammation, accelerating amyloid-β and tau protein accumulation characteristic of Alzheimer's disease. The research positions neuroinflammation as a central disease-modifying mechanism rather than merely a consequence of brain pathology. This metabolic-microbiome-neuroinflammation axis represents a paradigm shift from the traditional amyloid-focused approach to Alzheimer's, given the consistent failures of anti-amyloid therapies in clinical trials. The identification of omega-3 fatty acids and neural stem cell interventions as dual-action therapeutics targeting both immune signaling and microglial reprogramming offers promising multi-targeted strategies. For middle-aged adults, this finding underscores how maintaining healthy body weight and gut microbiome diversity through diet and lifestyle may serve as preventive measures against cognitive decline decades before symptoms appear, making metabolic health a critical component of brain longevity.