Decoding unchanged transcriptome of Alzheimer's disease reveals an NCAM1 mRNA switch as a potential biomarker

Alzheimer's disease (AD), a neurodegenerative disease primarily affecting older adults, is characterized by changes in memory, behavior, and language. Although gene expression varies during AD progression, the molecular mechanisms underlying this variation remain unclear. RNA sequencing indicates that most genes exhibit minimal gene-level differential expression in AD but may relate to neuronal function. Our comprehensive analysis revealed that neural cell adhesion molecule 1 (NCAM1) underwent alternative splicing (AS) in AD. Notably, an isoform switch occurred from the long isoform (L-NCAM1), typical under normal conditions, to the short isoform (S-NCAM1) in AD. S-NCAM1 lacked the intracellular domain in L-NCAM1. Additionally, the S-NCAM1-to-L-NCAM1 ratio increased in the hippocampus of amyloid precursor protein (<i>APP</i>)/PS1 mice compared to wild-type mice. Single-nucleus sequencing determined that this change in NCAM1 isoforms occurred predominantly within reactive astrocytes. Hence, AS may play a key role in AD development, while the L-NCAM1-to-S-NCAM1 ratio could serve as a biomarker.