The repeated failures of anti-amyloid therapies in Alzheimer's disease (AD) have exposed critical limitations of the linear amyloid cascade hypothesis and underscored the need for a broader etiological framework. The objective of this review is to synthesise mechanistic evidence for an exposome‑based model of sporadic AD that integrates metabolic, inflammatory, and sleep/circadian contributions to brain aging. Epidemiological evidence indicates that up to 40% of AD risk is attributable to modifiable environmental and lifestyle factors. These factors, collectively termed the aging exposome, represent the cumulative measure of external exposures and the body's biological responses across the lifespan. The central hypothesis is that sporadic AD emerges from the synergistic convergence of three interconnected exposome domains, metabolic dyshomeostasis, chronic neuroinflammation, and sleep/circadian disruption, which collectively lower the threshold for clinical dementia through shared molecular hubs like NF‑κB, mTOR, and ER stress. Central to this model is brain insulin resistance, which impairs cerebral glucose utilization, compromises mitochondrial oxidative phosphorylation, and disrupts lipid homeostasis via ceramide/sphingomyelin imbalance, collectively driving bioenergetic failure, oxidative stress, and enhanced amyloid-β production. Concurrently, peripherally derived and central inflammatory signals prime microglia, upregulate β-secretase (BACE1), and activate complement-mediated synaptic pruning, while emerging evidence suggests that sleep fragmentation and circadian misalignment are hypothesized to reduce glymphatic clearance and sustain BACE1 elevation, although direct causal evidence in humans remains limited. These ostensibly disparate pathways are integrated by shared molecular hubs, NF-κB, mTOR, and endoplasmic reticulum stress, which establish a self-reinforcing vicious cycle that selectively damages the hippocampus and default mode network. This cumulative aging exposome burden exerts its greatest impact during the midlife metabolic storm window (ages 40-60) and exhibits sex-specific vulnerability. Collectively, metabolic, inflammatory, and sleep deficits amplify each other via shared hubs; midlife is a critical, sex‑specific vulnerability window; and multi‑domain prevention is rational, though causal proof requires exposome‑wide and pragmatic trials. This reframes sporadic AD as an exposome‑driven syndrome, favoring simultaneous metabolic, immune, and sleep interventions over single‑target approaches.
