Alzheimer’s disease and progressive supranuclear palsy are both tauopathies, neurodegenerative conditions marked by the accumulation of insoluble hyperphosphorylated tau protein in the brain. Yet despite this shared pathological signature, the two illnesses diverge sharply in their clinical presentations and microscopic pathology, suggesting that overlapping and distinct molecular mechanisms drive each condition. A new genomic study, published in BMC Medical Genomics, has now mapped one layer of that molecular divergence in detail: exon skipping, a form of alternative splicing in which RNA transcripts drop entire coding segments during processing. The work identifies hundreds of genes whose splicing patterns differ between diseased and healthy brains, and separates changes common to both tauopathies from those unique to each.
The research team, led by Seonggyun Han, Nayeon Kang, Hilary Coon and Younghee Lee, performed transcriptomic analysis on RNA sequencing data from temporal cortex tissue. The discovery set comprised 82 Alzheimer’s disease patients, 84 progressive supranuclear palsy patients and 78 controls, while a replication set included 96 patients with each disease. Rather than measuring overall gene expression, the researchers focused specifically on differential exon skipping events, cataloguing genes in which individual exons were preferentially excluded from mature messenger RNA in disease tissue relative to controls. They then applied functional enrichment analysis to the resulting gene lists to identify the biological pathways in which disease-associated splicing changes clustered.
The scale of the splicing disruption proved substantial. Relative to controls, a total of 472 genes with exon skipping events were differentially spliced in Alzheimer’s disease and 366 in progressive supranuclear palsy. Strikingly, the majority of these changes were condition-specific: 325 of the Alzheimer’s-associated genes were unique to that disease and 219 were unique to progressive supranuclear palsy, while 147 genes showed altered exon skipping in both conditions. The shared set of genes was enriched in pathways related to neural activity and tau metabolism, including myelination, Schwann cell development and neurotrophin production, pointing to a common splicing-level signature of tauopathy in the temporal cortex.
The disease-specific gene sets told a complementary story. Genes with exon skipping changes exclusive to Alzheimer’s disease were enriched for synaptic activity, lipid metabolism and amyloid beta processing, connecting the splicing alterations to processes long implicated in that disorder’s pathology. By contrast, genes with altered skipping exclusive to progressive supranuclear palsy were enriched for the vesicle-mediated transport pathway, a distinct cellular process that may help explain why the two tauopathies follow such different clinical courses despite their shared tau pathology.
Beyond cataloguing splicing differences, the researchers probed their genetic underpinnings. They integrated whole-genome sequencing data from ascertained samples to investigate the cis-genetic regulators of the exon skipping events as splicing quantitative trait loci. This analysis identified three independent splicing quantitative trait loci, or cis-sQTLs, each associated with an exon skipping event in a different gene: c7orf63, DEF8 and HAP1. These loci represent inherited DNA variants that correlate with the probability that a nearby exon is skipped, offering candidate genetic mechanisms through which individual differences in RNA processing could contribute to tauopathy risk.
The study’s design carries both strengths and limitations worth noting. The work is also observational by nature: it identifies associations between disease status, splicing patterns and genetic variants, but does not establish that any of the detected exon skipping events cause neurodegeneration.
Even so, the findings sharpen a growing appreciation that alternative splicing, described by the authors as among the most important forms of transcriptional regulation in the brain, plays a role in distinguishing or unifying mechanisms across neurodegenerative diseases.
The authors frame their results as a step toward precision medicine for these conditions. By separating the conserved splicing signature shared by both tauopathies from the disease-specific changes in amyloid processing, lipid metabolism and vesicle transport, the study provides a molecular map that could guide future research into preventive strategies and treatment development. The three genetically regulated exon skipping events, in particular, offer concrete targets for follow-up studies aimed at determining whether inherited variation in RNA processing shapes who develops these devastating diseases.
Subject of Research: Exon-skipping splicing alterations in the temporal cortex associated with Alzheimer's disease and progressive supranuclear palsy
Article Title: Identification of exon-skipping splicing alterations associated with Alzheimer’s disease and progressive supranuclear palsy
Article References: Han, S., Kang, N., Coon, H., & Lee, Y. (2026). Identification of exon-skipping splicing alterations associated with Alzheimer’s disease and progressive supranuclear palsy. BMC Medical Genomics. https://doi.org/10.1186/s12920-026-02474-8
Image Credits: AI Generated
DOI: 10.1186/s12920-026-02474-8
Keywords: Alzheimer's disease, progressive supranuclear palsy, tauopathy, alternative splicing, exon skipping, RNA sequencing, splicing quantitative trait loci, temporal cortex, transcriptomics, neurodegeneration, whole-genome sequencing, tau protein
News Source: Diana Fleming. (October 27, 2026). Exon-Skipping Splicing Changes Distinguish Alzheimer’s Disease from Progressive Supranuclear Palsy. Scienmag.
