Abstract
Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive cognitive decline. According to the amyloid cascade hypothesis, amyloid-β (Aβ) accumulation plays a central role in initiating and driving AD progression. However, therapeutic strategies targeting Aβ have yielded limited and inconsistent clinical benefits, highlighting the need for broader, multitargeted approaches. Growing evidence identifies neuroinflammation as a central, disease-modifying mechanism in AD pathogenesis, supported by elevated inflammatory markers and immune-related genetic risk variants in patients. Multiple factors converge to sustain maladaptive neuroinflammation, including aging, genetic susceptibility, obesity, and the gut microbiota. Obesity, marked by white adipose tissue expansion and chronic low-grade systemic inflammation, promotes blood-brain barrier dysfunction and primes microglia toward proinflammatory phenotypes. In parallel, gut microbiota dysbiosis alters microbial metabolite production, increasing gut permeability, systemic endotoxemia, and neuroinflammatory signaling. Obesity is also associated with alterations in gut microbiota composition and metabolite profiles. Together, these metabolic and microbial cues mechanistically link peripheral dysfunction to central immune activation, accelerate amyloid and tau pathology, and are further amplified by genetic susceptibility and aging. This review synthesizes evidence connecting neuroinflammation with amyloid and tau pathology, emphasizing how obesity and gut microbiota dysbiosis amplify neuroinflammation and AD progression. We further evaluate 2 anti-inflammatory therapeutic strategies: omega-3 polyunsaturated fatty acids, which modulate immune signaling and gut microbiota composition, and neural stem cell-based interventions, which suppress neuroinflammation through paracrine immunomodulation and microglial reprogramming. By defining key drivers of pathological neuroinflammation and strategies to modulate them, this work provides a framework for developing innovative, multitargeted interventions that can be applied alone or in combination with classical antiamyloid therapies.