Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder driven by complex interactions between neuroinflammation, immune dysregulation, metabolic impairment, and disrupted synaptic plasticity. Emerging evidence highlights maladaptive microglial activation, chronic cytokine signaling (including IL-1β, TNF-α, and IL-6), and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity as pivotal contributors to neuronal damage and cognitive decline. Genetic studies further underscore the importance of immune and metabolic pathways, implicating key risk genes such as APOE, TREM2, and CR1, while deficits in autophagy exacerbate pathological protein aggregation, including amyloid-β and tau, ultimately accelerating synaptic loss. In this review, we synthesize molecular, genetic, and cellular evidence to clarify the mechanisms driving AD pathogenesis. We discuss genome-wide association study (GWAS) findings that define the genetic architecture of the disease, the neuroimmune crosstalk affecting memory-related brain regions, the link between chronic stress and amyloid pathology through HPA-axis dysregulation, and metabolic reprogramming in neurons, astrocytes, and microglia. Together, these interconnected processes highlight how dysregulated immunity and impaired protein clearance contribute to neuronal dysfunction and the progressive cognitive decline characteristic of AD.