This study has several limitations. We only characterize splicing events in one region (the DLPFC) of the aging brain. The DLPFC is a region that is affected by amyloid pathology relatively early as it spreads throughout the neocortex47. The accumulation of Tau pathology progresses in a stereotypic manner captured by the Braak stages48, and the DLPFC displays accumulation of NFTs containing Tau typically when individuals begin to be symptomatic. Thus, both amyloid and Tau pathology accumulate in the DLPFC in Alzheimer’s disease, and we use quantitative measures of these pathologies to enhance our power in discovering the molecular features that are associated with these pathologies. Some of these splicing changes may contribute to the accumulation of these pathologies while others may be a reaction to the presence of pathology or may be the result of indirect effects of the pathology in other brain regions. Currently, we cannot differentiate these three sources of variation in our results. Expression datasets from multiple brain regions exist in the GTEx project49, but the sample size is small (n=88–136) to build a robust transcriptome model
