Title: The UNC13A cryptic exon associates with cognitive impairment in Alzheimer’s disease

Abstract: TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where its co-occurrence with amyloid β plaques and tau neurofibrillary tangles 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 lobar degeneration (FTLD) by weakening TDP-43 binding promoting CE inclusion. Here, we evaluated the rs12973192 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, and investigated the influence of the UNC13A CE on TDP-43 pathology, survival and cognitive impairment in AD. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the rs12973192 UNC13A CE SNP and dementia diagnosis.

NOTE: Please watch video for walkthrough of the poster. For any questions please do not hesitate to reach out to: Mercedes Prudencio, mxp2730@miami.edu