Reframing Alzheimer’s Disease Pathogenesis from the Amyloid Cascade Hypothesis to Mitochondrial PINK1 Centric Perspective

With the recent advances in anti-amyloid therapies, disease-modifying strategies for Alzheimer’s disease (AD) have largely focused on the amyloid cascade hypothesis. However, the optimal therapeutic interventions remains a matter of ongoing debate. It is still unclear whether targeting the amyloid cascade alone is sufficient or if a multitargeted therapeutic approach is obligatory. This question remains particularly important; given that effective long-term disease-modifying therapies for AD continue to be limited. Strong genetic evidence from AD involving mutations in APP , PSEN1 , and PSEN2 supports a causal role for the early-onset familial AD. However, most Alzheimer’s cases are sporadic and likely to arise from multifactorial cellular stress pathways that extend beyond amyloid accumulation alone. Increasing evidence suggests that, particularly in sporadic AD, Aβ accumulation may also reflect a downstream consequence of neuronal stress rather than its sole initiating event. Mitochondrial dysfunction, oxidative stress, lysosomal dysfunction, blood-brain barrier (BBB) rupture, microglial transition states and impaired protein clearance are now recognized as early and interconnected cascade of signalling events in AD pathogenesis. In this context, PTEN-induced kinase 1 (PINK1), a central regulator of mitophagy, has gained attention for its role in maintaining mitochondrial and cellular homeostasis. From this viewpoint, we propose the hypothesize that PINK1 could be a direct “amyloid switch” that can be considered as a part of broader cellular resilience cascading signalling event.