Project Summary Somatic mutations in the brains of patients with Alzheimer’s disease (AD) and other neurological disorders have been established as a potential mechanism for their pathophysiology. One class of mutations arise from sporadic mosaicism of retrotransposons, endogenous elements that can mobilize and insert copies into new genomic locations and have been implicated in the progression of various cancers and disease. Somatic insertions of retrotransposons are prevalent in individual neurons in the cerebral cortex of the human brain, a region long associated with AD progression, and recent work has shown a connection between AD-associated Tau protein mediated mechanisms with retrotransposition activity and somatic mutations. Unfortunately, even though the apparent association with disease is strong, these types of elements are often ignored in analyses. Because of their repetitive nature, they have been hard to measure with short read sequencing technologies and any whole- genome, long-read sequencing technologies have been too costly to apply. In this proposal, we build on the technology of our parent grant to capture a set of actively moving transposable elements: L1Hs, AluYa5/8, AluYb8/9, and SVAs. These represent the vast majority of active transposable elements and thus will allow us to measure the genetic diversity of polymorphic insertions of these elements. After capture, we will use nanopore long-read sequencing to capture both the entire insertion as well as thousands of bases of surrounding sequence which will allow for accurate mapping of these elements to the genome. We will apply this technology to multiple regions from 30 AD brains to allow for follow-up analysis of the enrichment and effect of transposable elements in AD.