Abstract

Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by the extracellular accumulation of amyloid-beta (Abeta) plaques and the formation of intracellular neurofibrillary tau tangles; however, the prevailing scientific paradigm has shifted toward an integrative model of pathogenesis that recognizes neuroinflammation as a critical, self-perpetuating driver of cognitive attrition. This multifaceted interplay is mediated by the brain–body axis, wherein chronic systemic inflammation—stemming from metabolic dysfunction, cardiovascular disease, or environmental stressors such as fine particulate matter PM2.5—compromises the structural integrity of the blood–brain barrier. Methods: Such environmental insults serve as priming agents for the innate immune system, shifting peripheral immune populations toward a pro-inflammatory phenotype that is further exacerbated by the stabilization of hypoxia-inducible factors (HIFs) through oxidative stress-induced pseudohypoxia, even under normoxic conditions. Results: The subsequent activation of microglia and astrocytes transitions the cerebral microenvironment from a homeostatic, neurosupportive state into a neurotoxic milieu that actively promotes synaptic loss and neuronal death. Conclusions: Consequently, contemporary research has pivoted from broad-spectrum anti-inflammatory interventions toward targeted immune modulation, emphasizing that a comprehensive understanding of how systemic dysfunction perpetuates neuroinflammatory cascades is essential for developing efficacious therapies capable of attenuating AD progression and mitigating its global health burden.

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