In this study, we directly examined alternative splicing events in a large dataset of aging brains, which led to both the observation that specific alternative splicing events are reproducibly associated with Alzheimer’s disease and that certain validated genetic associations affect splicing of a nearby gene as the proximal functional consequence of the susceptibility allele. Our replication efforts demonstrate that the observed Alzheimer’s disease-related perturbations in splicing are not simply due to spliceosomal failure: specific genes are reproducibly affected in a specific manner. Further, results from our in vitro model of tau overexpression in iPSC-derived neurons suggest that perturbation of MAPT may be sufficient to cause at least a subset of these disease-related splicing changes that are observed in the human cortex at autopsy.
