Somatic genomic variability that may provide mechanistic insights into posterior cortical atrophy (PCA) Lead Investigator: Yun Yung Institution : The Scripps Research Institute E-Mail : yyung@scripps.edu Proposal ID : 719 Proposal Description: Somatic genomic variability may provide mechanistic insights into posterior cortical atrophy (PCA), which most commonly occurs as an early onset variant of sporadic Alzheimer?s disease (SAD). We have recently reported finding neuronal genomic mosaicism (NGM) in SAD, wherein individual SAD neurons show significantly increased ranges and amounts of genomic DNA, accompanied by mosaic increasees in amyloid precursor protein gene (APP) copy number variation (CNV) (2015 Bushman and Kaeser, eLife). NGM in SAD is very prominent in neurons of the prefrontal cortex, while PCA preferentially affects posterior (occipital and parietal) cortical neurons, and its etiology has not been explained. We will test the hypothesis that PCA neurons are enriched in SAD-related forms of NGM including APP CNVs, preferentially increased in occipital over temporal and prefrontal cortex as well as cerebellum, using a variety of techniques that include examining DNA content variation, copy number variation through small sample sequencing, and bioinformatic analyses.