Alternative splicing in Alzheimer's disease: Driver, modifier, or consequence of neurodegeneration

Alzheimer's disease (AD) is a complex neurodegenerative disorder in which the molecular mechanisms driving onset and progression remain incompletely understood. Emerging evidence highlights RNA splicing as a central regulatory axis shaping neuronal function and vulnerability. In this review, we examine how disruptions in alternative splicing contribute to AD pathogenesis by altering transcript isoform diversity across key genes, including APP, MAPT, PSEN1/2, and BACE1. We discuss how aging, oxidative stress, neuroinflammation, and cellular stress responses converge to impair spliceosomal fidelity and RNA-binding protein function. These alterations lead to isoform imbalance, protein dysfunction, and synaptic impairment, ultimately promoting neurodegeneration. Importantly, we critically address whether splicing dysregulation represents a primary driver or a downstream consequence of disease. Finally, we explore emerging therapeutic strategies targeting RNA processing, including antisense oligonucleotides and RNA-based technologies, highlighting their potential to restore transcriptomic balance and modify disease progression.