Alzheimer's disease pathogenesis re-evaluated: Synaptic dysfunction and glutamate excitotoxicity precede amyloid toxicity

Alzheimer's disease (AD) remains a devastating neurodegenerative disorder, with current therapies offering limited efficacy. Decades of research have focused on β-amyloid (Aβ) peptides as the primary driver, yet numerous anti-amyloid therapies have failed in clinical trials, highlighting critical gaps in understanding early pathogenic mechanisms. This suggests the need to re-evaluate the causal chain, moving beyond a sole focus on amyloid accumulation to consider other upstream events that initiate neuronal damage and cognitive decline. Understanding these earlier processes, such as synaptic dysfunction and glutamate excitotoxicity, could unlock more effective preventive and therapeutic strategies.

This comprehensive review systematically analyzed and synthesized emerging evidence from a broad range of preclinical and clinical studies to re-evaluate the traditional amyloid-centric model of Alzheimer's disease (AD). Researchers critically assessed findings from in vitro neuronal cultures, in vivo animal models, and human neuroimaging studies, focusing on the interplay between synaptic health, glutamate signaling, and metabolic function. The review's methodology involved integrating recent data on glutamate dysregulation with established amyloid and tau pathology, aiming to construct a multifactorial model that explains the limitations of current amyloid-targeting interventions and proposes new therapeutic avenues.

The review proposes a fundamental re-evaluation of Alzheimer's disease (AD) pathogenesis, shifting focus from amyloid as the primary driver to synaptic dysfunction coupled with glutamate excitotoxicity and neurometabolic failure. Emerging evidence demonstrates that neuronal hyperactivity and glutamate excitotoxicity can contribute to synaptic damage at preclinical AD stages, potentially independent of amyloid deposition. The authors introduce a metabolic-energetic framework, suggesting that chronic neuronal burden from metabolic overload, rather than amyloid toxicity alone, may trigger a cascade of synaptic deterioration and neuronal death. This model integrates glutamate dysregulation with amyloid and tau pathology, emphasizing the temporal primacy and mechanistic interplay of excitotoxicity in early synaptic dysfunction. They argue that intervening at the level of downstream synaptic damage, such as amyloid removal, is often too late for effective treatment.

This reframing suggests that targeting synaptic health and glutamate homeostasis before irreversible amyloid-driven damage may yield more effective preventive strategies than current approaches.