Association of short tandem repeats with neuropathological features in late‐onset of Alzheimer’s disease brains

Background Late-Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there no single model explaining the mode of inheritance. Short tandem repeats (STRs), which are hyper-mutable sequences in human genome could explain some missing heritability LOAD. STRs involved several neuro-degenerative disorders. We systematically evaluated impact 31 disease-associated on neuropathological LOAD features. Method From whole-genome sequencing (WGS) data for 1,134 unrelated individuals European ancestry from Religious Orders Study (ROS) Rush Memory Aging project (MAP) cohorts, we identified known pathogenic loci using ExpansionHunter. WGS was generated DNA extracted blood brain tissues. tested association with a) status, b) beta-amyloid levels, c) neurofibrillary tangle (NFT) burden, d) global measure pathology based scaled scores 5 regions e) estimated slope cognition longitudinal measurements. Regression models adjusting age, sex first three principal components. Subsequently, examined if influenced gene expression dorsolateral prefrontal cortex (DLPFC), posterior cingulate (PCC) anterior (AC) traits were mediated altered expression. Result TGC repeat ATXN1 associated cognitive decline (b = -0.007, p 0.014) risk clinical AD 0.126, 0.03). Variation CAG ATN1 0.004, 0.022) pathological -0.069, 0.035). Longer Repeats at increased DLPFC 0.012, 0.049) PCC 0.019, 0.006) 0.01, 0.016) 0.026) Mediation analysis determined that effect tau (p 0.004). Conclusion demonstrate disease causing influence underlying endophenotypes AD. This suggests