Rethinking early Alzheimer's disease: An impaired internal model updating disorder?

Although sporadic Alzheimer's disease (AD) has long been conceptualized primarily within a molecular framework centered on amyloid-β and hyperphosphorylated tau pathology, this perspective does not fully explain the early vulnerability of specific brain networks or the emergence of non-cognitive symptoms, even decades before memory decline. The present review directly addresses this question by proposing an integrative, systems-level, translational framework that links age-related sensory dysfunction-most notably olfactory impairment-to the failure of predictive sensorimotor internal models and to early network instability. Persistent prediction-error mismatch could impose sustained compensatory demands on key neuromodulatory and adaptive control hubs involved in internal model updating, particularly the locus coeruleus and the cerebellum. Their widespread connectivity and pivotal function in modulating plasticity and network interactions may render them particularly vulnerable to chronic hyperactivity. Over time, this compensatory state may contribute to maladaptive plasticity, neuroinflammation, and conditions that facilitate the progressive accumulation and propagation of AD hallmarks across interconnected networks, including the medial temporal, sleep-regulatory, autonomic, and affective circuits. This perspective offers a hypothesis-driven, mechanistic, systems-level framework for the early emergence of non-cognitive AD manifestations, including olfactory dysfunction, sleep disturbances, autonomic dysregulation, and affective symptoms. Accordingly, these features may provide promising avenues for improving early risk stratification and identifying individuals in preclinical disease stages. Importantly, interventions targeting sensory processing, neuromodulatory balance, and sleep regulation may represent potential early disease-modifying strategies.