• Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016).

    CAS  Article  Google Scholar 

  • Hyman, B. T. et al. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 8, 1–13 (2012).

    Article  Google Scholar 

  • Braak, H. & Braak, E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol. Aging 16, 271–278 (1995).

    CAS  Article  Google Scholar 

  • Gabbita, S. P., Lovell, M. A. & Markesbery, W. R. Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J. Neurochem. 71, 2034–2040 (1998).

    CAS  Article  Google Scholar 

  • Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).

    CAS  Article  Google Scholar 

  • Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    CAS  Article  Google Scholar 

  • Osorio, F. G. et al. Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis. Cell Rep. 25, 2308–2316 (2018).

    CAS  Article  Google Scholar 

  • Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  Article  Google Scholar 

  • Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015).

    CAS  Article  Google Scholar 

  • Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    CAS  Article  Google Scholar 

  • Lu, T. et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature 507, 448–454 (2014).

    CAS  Article  Google Scholar 

  • Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    Article  Google Scholar 

  • Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    CAS  Article  Google Scholar 

  • Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS  Article  Google Scholar 

  • Lodato, M. A. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015).

    CAS  Article  Google Scholar 

  • Hazen, J. L. et al. The complete genome sequences, unique mutational spectra, and developmental potency of adult neurons revealed by cloning. Neuron 89, 1223–1236 (2016).

    CAS  Article  Google Scholar 

  • Bhagwat, A. S. et al. Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli. Proc. Natl Acad. Sci. USA 113, 2176–2181 (2016).

    CAS  Article  Google Scholar 

  • Kucab, J. E. et al. A compendium of mutational signatures of environmental agents. Cell 177, 821–836 (2019).

    CAS  Article  Google Scholar 

  • Sala Frigerio, C. et al. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer’s disease patients. Alzheimers Dement. 11, 1265–1276 (2015).

    Article  Google Scholar 

  • Abascal, F. et al. Somatic mutation landscapes at single-molecule resolution. Nature 593, 405–410 (2021).

    CAS  Article  Google Scholar 

  • Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat. Neurosci. 22, 47–56 (2019).

    CAS  Article  Google Scholar 

  • Leng, K. et al. Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat. Neurosci. 24, 276–287 (2021).

    CAS  Article  Google Scholar 

  • Bohrson, C. L. et al. Linked-read analysis identifies mutations in single-cell DNA-sequencing data. Nat. Genet. 51, 749–754 (2019).

    CAS  Article  Google Scholar 

  • Petljak, M. et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis. Cell 176, 1282–1294 (2019).

    CAS  Article  Google Scholar 

  • Xing, D., Tan, L., Chang, C.-H., Li, H. & Xie, X. S. Accurate SNV detection in single cells by transposon-based whole-genome amplification of complementary strands. Proc. Natl Acad. Sci. USA 118, e2013106118 (2021).

    CAS  Article  Google Scholar 

  • Madabhushi, R. et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161, 1592–1605 (2015).

    CAS  Article  Google Scholar 

  • Min, S. et al. Absence of coding somatic single nucleotide variants within well-known candidate genes in late-onset sporadic Alzheimer’s disease based on the analysis of multi-omics data. Neurobiol. Aging 108, 207–209 (2021).

    CAS  Article  Google Scholar 

  • Lee, M. H. et al. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563, 639–645 (2018).

    CAS  Article  Google Scholar 

  • Kim, J. et al. APP gene copy number changes reflect exogenous contamination. Nature 584, E20–E28 (2020).

    CAS  Article  Google Scholar 

  • Jager, M. et al. Deficiency of nucleotide excision repair is associated with mutational signature observed in cancer. Genome Res. 29, 1067–1077 (2019).

    CAS  Article  Google Scholar 

  • Mecocci, P., MacGarvey, U. & Beal, M. F. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann. Neurol. 36, 747–751 (1994).

    CAS  Article  Google Scholar 

  • Chun, H. et al. Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2 production. Nat. Neurosci. 23, 1555–1566 (2020).

    CAS  Article  Google Scholar 

  • Pao, P. C. et al. HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease. Nat. Commun. 11, 2484 (2020).

    CAS  Article  Google Scholar 

  • Nouspikel, T. & Hanawalt, P. C. Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Mol. Cell. Biol. 20, 1562–1570 (2000).

    CAS  Article  Google Scholar 

  • Seplyarskiy, V. B. et al. Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations. Nat. Genet. 51, 36–41 (2019).

    CAS  Article  Google Scholar 

  • Huang, J. C., Svoboda, D. L., Reardon, J. T. & Sancar, A. Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5′ and the 6th phosphodiester bond 3′ to the photodimer. Proc. Natl Acad. Sci. USA 89, 3664–3668 (1992).

    CAS  Article  Google Scholar 

  • Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).

    CAS  Article  Google Scholar 

  • Soheili-Nezhad, S., van der Linden, R. J., Olde Rikkert, M., Sprooten, E. & Poelmans, G. Long genes are more frequently affected by somatic mutations and show reduced expression in Alzheimer’s disease: Implications for disease etiology. Alzheimers Dement. 17, 489–499 (2020).

    Article  Google Scholar 

  • Crabtree, G. R. Our fragile intellect. Part I. Trends Genet. 29, 1–3 (2013).

    CAS  Article  Google Scholar 

  • Fragola, G. et al. Deletion of topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nat. Commun. 11, 1962 (2020).

    CAS  Article  Google Scholar 

  • Gonzalez-Pena, V. et al. Accurate genomic variant detection in single cells with primary template-directed amplification. Proc. Natl Acad. Sci. USA 118, e2024176118 (2021).

    CAS  Article  Google Scholar 

  • Luquette, L. J. et al. Ultraspecific somatic SNV and indel detection in single neurons using primary template-directed amplification. Preprint at bioRxiv https://doi.org/10.1101/2021.04.30.442032 (2021).

  • Kaur, U. et al. Reactive oxygen species, redox signaling and neuroinflammation in Alzheimer’s disease: the NF-κB connection. Curr. Top. Med. Chem. 15, 446–457 (2015).

    CAS  Article  Google Scholar 

  • Butterfield, D. A., Castegna, A., Lauderback, C. M. & Drake, J. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol. Aging 23, 655–664 (2002).

    Article  Google Scholar 

  • David, D. C. et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J. Biol. Chem. 280, 23802–23814 (2005).

    CAS  Article  Google Scholar 

  • Khurana, V. et al. A neuroprotective role for the DNA damage checkpoint in tauopathy. Aging Cell 11, 360–362 (2012).

    CAS  Article  Google Scholar 

  • Sakofsky, C. J. et al. Repair of multiple simultaneous double-strand breaks causes bursts of genome-wide clustered hypermutation. PLoS Biol. 17, e3000464 (2019).

    CAS  Article  Google Scholar 

  • Mandrekar-Colucci, S. & Landreth, G. E. Microglia and inflammation in Alzheimer’s disease. CNS Neurol. Disord. Drug Targets 9, 156–167 (2010).

    CAS  Article  Google Scholar 

  • Rottkamp, C. A. et al. Redox-active iron mediates amyloid-beta toxicity. Free Radic. Biol. Med. 30, 447–450 (2001).

    CAS  Article  Google Scholar 

  • Huang, A. Y. et al. Parallel RNA and DNA analysis after deep sequencing (PRDD-seq) reveals cell type-specific lineage patterns in human brain. Proc. Natl Acad. Sci. USA 117, 13886–13895 (2020).

    CAS  Article  Google Scholar 

  • Dean, F. B., Nelson, J. R., Giesler, T. L. & Lasken, R. S. Rapid amplification of plasmid and phage DNA using Phi 29 DNA polymerase and multiply-primed rolling circle amplification. Genome Res. 11, 1095–1099 (2001).

    CAS  Article  Google Scholar 

  • Evrony, G. D. et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151, 483–496 (2012).

    CAS  Article  Google Scholar 

  • Zheng, G. X. Y. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).

    CAS  Article  Google Scholar 

  • Fan, J. et al. Characterizing transcriptional heterogeneity through pathway and gene set overdispersion analysis. Nat. Methods 13, 241–244 (2016).

    CAS  Article  Google Scholar 

  • Dong, X. et al. Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat. Methods 14, 491–493 (2017).

    CAS  Article  Google Scholar 

  • Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  Article  Google Scholar 

  • McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    CAS  Article  Google Scholar 

  • Keogh, M. J. et al. High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nat. Commun. 9, 4257 (2018).

    Article  Google Scholar 

  • Park, J. S. et al. Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation. Nat. Commun. 10, 3090 (2019).

    Article  Google Scholar 

  • Luquette, L. J., Bohrson, C. L., Sherman, M. A. & Park, P. J. Identification of somatic mutations in single cell DNA-seq using a spatial model of allelic imbalance. Nat. Commun. 10, 3908 (2019).

    Article  Google Scholar 

  • Cai, X. et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 8, 1280–1289 (2014).

    CAS  Article  Google Scholar 

  • Baslan, T. et al. Genome-wide copy number analysis of single cells. Nat. Protoc. 7, 1024–1041 (2012).

    CAS  Article  Google Scholar 

  • Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Campbell, P. J. & Stratton, M. R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3, 246–259 (2013).

    CAS  Article  Google Scholar 

  • Blokzijl, F., Janssen, R., van Boxtel, R. & Cuppen, E. MutationalPatterns: comprehensive genome-wide analysis of mutational processes. Genome Med. 10, 33 (2018).

    Article  Google Scholar 

  • Kim, J. et al. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat. Genet. 48, 600–606 (2016).

    CAS  Article  Google Scholar 

  • Bates, D., Mächler, M., Bolker, B. & Walker, S. Fitting linear mixed-effects models using lme4. J. Stat. Softw. 67, 1–48 (2015).

    Article  Google Scholar 

  • Kuznetsova, A., Brockhoff, P. B. & Christensen, R. H. B. lmerTest Package: tests in linear mixed effects models. J. Stat. Softw. 82, 1–26 (2017).

    Article  Google Scholar 

  • Consortium, G. T. et al. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).

    Article  Google Scholar 

  • Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article  Google Scholar 

  • Young, M. D., Wakefield, M. J., Smyth, G. K. & Oshlack, A. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol. 11, R14 (2010).

    Article  Google Scholar 

  • Green, P. et al. Transcription-associated mutational asymmetry in mammalian evolution. Nat. Genet. 33, 514–517 (2003).

    CAS  Article  Google Scholar 

  • Polak, P. & Arndt, P. F. Transcription induces strand-specific mutations at the 5′ end of human genes. Genome Res. 18, 1216–1223 (2008).

    CAS  Article  Google Scholar 

  • Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  Google Scholar 

  • Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

    CAS  Article  Google Scholar 

  • Coppede, F. & Migliore, L. DNA damage and repair in Alzheimer’s disease. Curr. Alzheimer Res. 6, 36–47 (2009).

    CAS  Article  Google Scholar 

  • Hoang, M. L. et al. Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. Proc. Natl Acad. Sci. USA 113, 9846–9851 (2016).

    CAS  Article  Google Scholar 

  • Franco, I. et al. Somatic mutagenesis in satellite cells associates with human skeletal muscle aging. Nat. Commun. 9, 800 (2018).

    Article  Google Scholar 

  • Zhang, L. et al. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc. Natl Acad. Sci. USA 116, 9014–9019 (2019).

    CAS  Article  Google Scholar 

  • Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).

    CAS  Article  Google Scholar 

  • Franco, I. et al. Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type. Genome Biol. 20, 285 (2019).

    CAS  Article  Google Scholar 

  • Brunet, J. P., Tamayo, P., Golub, T. R. & Mesirov, J. P. Metagenes and molecular pattern discovery using matrix factorization. Proc. Natl Acad. Sci. USA 101, 4164–4169 (2004).

    CAS  Article  Google Scholar