APP gene copy number changes reflect exogenous contamination

Various types of somatic mutations occur in cells of the human body and cause human diseases, including cancer and some neurological disorders¹. Recently, Lee et al.² (hereafter ‘the Lee study’) reported somatic copy number gains of the APP gene, a known risk locus for Alzheimer’s disease (AD), in 69% and 25% of neurons of AD patients and controls, respectively, and argued that the mechanism of these copy number gains was somatic integration of APP mRNA into the genome, creating what they called genomic cDNA (gencDNA). Our reanalysis of the data from the Lee study and two additional whole-exome sequencing (WES) data sets by the authors of the Lee study³ and Park et al.⁴ revealed evidence that APP gencDNA originates mainly from exogenous contamination by APP recombinant vectors, nested PCR products, and human and mouse mRNA, respectively, rather than from true somatic integration of endogenous APP. We further present our own single-cell whole-genome sequencing (scWGS) data that show no evidence for somatic APP retrotransposition in neurons from individuals with AD or from healthy individuals of various ages.