Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterised by cognitive decline, behavioural disturbances, and widespread neuronal loss. Despite extensive research, the underlying pathogenic mechanisms remain incompletely understood, and no effective disease-modifying treatments are currently available. Emerging evidence implicates dysregulated β-amyloid (Aβ) and tau metabolism as key contributors to AD pathogenesis, with growing attention focused on the roles of autophagy and apoptosis in mediating neuronal vulnerability. The autophagy–lysosome pathway (ALP) is the principal intracellular degradation mechanism responsible for clearing misfolded and aggregated proteins, damaged organelles, and maintaining cellular homeostasis. Apoptosis, on the other hand, represents a tightly controlled form of programmed cell death that, when aberrantly activated, contributes to excessive neuronal loss and neuroinflammation. In this review, we comprehensively examine the complex interplay between autophagy and apoptosis in AD and highlight the regulatory roles of major signalling pathways, including PI3K/Akt/mTOR, AMPK, SIRT1, p38 MAPK, NLRP3/caspase-1, and PINK1/Parkin. We discuss how disruptions in these pathways alter autophagic flux, impair mitochondrial quality control, exacerbate Aβ and tau pathology, and amplify inflammatory responses. Special emphasis is placed on the dual role of these pathways in modulating both survival and death signals within neuronal cells. By integrating mechanistic insights across multiple signalling axes, this review underscores the therapeutic potential of targeting autophagy–apoptosis crosstalk to restore cellular homeostasis and mitigate neurodegeneration. Clarifying these mechanisms may provide a foundation for novel, pathway-specific interventions to slow or halt AD progression.
Cui et al. (Tue,) studied this question.