Revisiting Alzheimer’s Disease Mechanisms: Amyloid Dynamics, and Emerging Insights

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction, glial cell activation, and deterioration of neurons. Multiple pathways contribute to its pathophysiology, including β-amyloid (Aβ) plaque formation, intracellular neurofibrillary tangles, oxidative neuronal damage, and inflammatory responses. While Aβ deposition is considered an early trigger in the disease cascade, clinical symptom progression correlates more strongly with tau pathology and inflammatory responses. Recent concerns over data integrity in several high-profile AD studies have prompted critical re-evaluations of widely accepted hypotheses, emphasizing the urgent need for scientific transparency, reproducibility, and independent validation. In compiling this review, we prioritized findings supported by converging evidence from multiple experimental approaches and replication across independent cohorts. The hypothesis that an imbalance between Aβ42 synthesis and clearance is a central factor in AD has gained support from recent evidence, despite ongoing debate over the amyloid β-protein hypothesis. Dominant mutations associated with early-onset AD are primarily found in the amyloid precursor protein, which serves as the substrate for Aβ production, or in presenilin, the protease responsible for Aβ formation. The identification of presenilin as the catalytic site for β-secretase has provided crucial insights into AD pathogenesis. This review synthesizes current understanding of AD mechanisms, highlights emerging insights from multi-omics and spatial transcriptomic technologies, and discusses the evolving therapeutic landscape. Despite setbacks, the field continues to advance through methodological innovation and a revived interest in AD research integrity, offering hope for early diagnosis, more targeted treatments, and ultimately, disease-modifying therapies.