| Title: | The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease |
| Journal: | Alzheimer's Research & Therapy |
| Published: | 14 Aug 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42596024/ |
| DOI: | https://doi.org/10.1186/s13195-026-02157-7 |
| URL: | https://link.springer.com/content/pdf/10.1186/s13195-026-02157-7.pdf |
Publication 21009
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Abstract
BackgroundTAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion.ObjectiveTo investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD.MethodsWe evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis.ResultsIn AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2-another well-known CE target-exhibited no such association.ConclusionsThese findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.</p>
13 Keywords
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Brain
- Cohort Studies
- DNA-Binding Proteins
- Exons
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Nerve Tissue Proteins
- Polymorphism, Single Nucleotide
27 Authors
- Madison M. Reeves
- Sara Aviles Carpintero
- Matteo Zanovello
- Karen Jansen-West
- Mei Yue
- Anna Calliari
- Yuping Song
- Judith Dunmore
- Candela Maroto Cidfuentes
- Sophie Ball
- Jennifer M. Kachergus
- Heather E. Killeen
- Bailey Rawlinson
- Erica Engelberg-Cook
- Michael DeTure
- Gregory S. Day
- Neill R. Graff-Radford
- Bradley F. Boeve
- David S. Knopman
- Ronald C. Petersen
- Melissa Murray
- Aubrey E. Thompson
- Dennis W. Dickson
- Pietro Fratta
- Leonard Petrucelli
- Keith A. Josephs
- Mercedes Prudencio
1 Application
| Application ID | Title |
|---|---|
| 92363 | Clinical and molecular heterogeneity of Kennedy's disease |
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