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Early-onset familial Alzheimer\u2019s disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and alternative splicing of these two genes has been implicated in both familial and sporadic Alzheimer\u2019s disease. Here, we leveraged targeted isoform-sequencing to characterize thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic Alzheimer\u2019s disease, familial Alzheimer\u2019s disease (carrying PSEN1 and PSEN2 variants), and controls. Our results reveal alternative splicing patterns of PSEN2 specific to sporadic Alzheimer\u2019s disease, including a human-specific cryptic exon present in intron 9 of PSEN2 as well as a 77 bp intron retention product before exon 6 that are both significantly elevated in sporadic Alzheimer\u2019s disease samples, alongside a significantly lower percentage of canonical full-length PSEN2 transcripts versus familial Alzheimer\u2019s disease samples and controls. Both alternatively spliced products are predicted to generate a prematurely truncated PSEN2 protein and were corroborated in an independent cerebellum RNA-sequencing dataset. In addition, our data in PSEN variant carriers is consistent with the hypothesis that PSEN1 and PSEN2 variants need to produce full-length but variant proteins to contribute to the onset of Alzheimer\u2019s disease, although intriguingly there were far fewer full-length transcripts carrying pathogenic alleles versus wild-type alleles in PSEN2 variant carriers. Finally, we identify frequent RNA editing at Alu elements present in an extended 3\u2032 untranslated region in PSEN2. Overall, this work expands the understanding of PSEN1 and PSEN2 variants in Alzheimer\u2019s disease, shows that transcript differences in PSEN2 may play a role in sporadic Alzheimer\u2019s disease, and suggests novel mechanisms of Alzheimer\u2019s disease pathogenesis.<\/jats:p>","DOI":"10.1093\/brain\/awac294","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T01:07:39Z","timestamp":1660180059000},"page":"507-518","source":"Crossref","is-referenced-by-count":36,"title":["Aberrant splicing of\n                    <i>PSEN2<\/i>\n                    , but not\n                    <i>PSEN1<\/i>\n                    , in individuals with sporadic Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"146","author":[{"given":"Meredith M","family":"Course","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, University of Washington School of Medicine , Seattle, WA 98195 , USA"},{"name":"Department of Molecular Biology, Colorado College , Colorado Springs, CO 80903 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Gudsnuk","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, University of Washington School of Medicine , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Dirk","family":"Keene","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D","family":"Bird","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, University of Washington School of Medicine , Seattle, WA 98195 , USA"},{"name":"Northwest Mental Illness Research, Education and Clinical Centers, VA Puget Sound Health Care System , Seattle, WA 98108 , USA"},{"name":"Geriatrics Research Education and Clinical Center, Puget Sound VA Medical Center , Seattle, WA 98108 , USA"},{"name":"Department of Neurology, University of Washington School of Medicine , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Jayadev","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, University of Washington School of Medicine , Seattle, WA 98195 , USA"},{"name":"Department of Neurology, University of Washington School of Medicine , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8840-6969","authenticated-orcid":false,"given":"Paul N","family":"Valdmanis","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, University of Washington School of Medicine , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"2023052502593790800_awac294-B1","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/349704a0","article-title":"Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease","volume":"349","author":"Goate","year":"1991","journal-title":"Nature"},{"key":"2023052502593790800_awac294-B2","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1126\/science.7638622","article-title":"Candidate gene for the chromosome 1 familial Alzheimer\u2019s disease locus","volume":"269","author":"Levy-Lahad","year":"1995","journal-title":"Science"},{"key":"2023052502593790800_awac294-B3","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/375754a0","article-title":"Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's 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peptide seeds","volume":"90","author":"Veugelen","year":"2016","journal-title":"Neuron"},{"key":"2023052502593790800_awac294-B7","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.cell.2017.07.004","article-title":"Alzheimer\u2019s-causing mutations shift abeta length by destabilizing gamma-secretase-abetan interactions","volume":"170","author":"Szaruga","year":"2017","journal-title":"Cell"},{"key":"2023052502593790800_awac294-B8","volume-title":"GeneReviews\u00ae","author":"Bird","year":"2018"},{"key":"2023052502593790800_awac294-B9","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s00401-012-0996-2","article-title":"The genetics and neuropathology of Alzheimer\u2019s disease","volume":"124","author":"Schellenberg","year":"2012","journal-title":"Acta Neuropathol"},{"key":"2023052502593790800_awac294-B10","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.jalz.2016.01.012","article-title":"Molecular genetics of early-onset Alzheimer\u2019s disease revisited","volume":"12","author":"Cacace","year":"2016","journal-title":"Alzheimers Dement"},{"key":"2023052502593790800_awac294-B11","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/mp.2012.15","article-title":"High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease","volume":"17","author":"Pottier","year":"2012","journal-title":"Mol Psychiatry"},{"key":"2023052502593790800_awac294-B12","doi-asserted-by":"crossref","first-page":"e31039","DOI":"10.1371\/journal.pone.0031039","article-title":"Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer\u2019s disease families","volume":"7","author":"Cruchaga","year":"2012","journal-title":"PLoS ONE"},{"key":"2023052502593790800_awac294-B13","doi-asserted-by":"crossref","first-page":"e1002270","DOI":"10.1371\/journal.pmed.1002270","article-title":"APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases","volume":"14","author":"Lanoiselee","year":"2017","journal-title":"PLoS Med"},{"key":"2023052502593790800_awac294-B14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/sj.embor.7400897","article-title":"Loss-of-function presenilin mutations in Alzheimer disease. Talking point on the role of presenilin mutations in Alzheimer disease","volume":"8","author":"De Strooper","year":"2007","journal-title":"EMBO Rep"},{"key":"2023052502593790800_awac294-B15","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1093\/brain\/awq033","article-title":"Alzheimer\u2019s disease phenotypes and genotypes associated with mutations in presenilin 2","volume":"133","author":"Jayadev","year":"2010","journal-title":"Brain"},{"key":"2023052502593790800_awac294-B16","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1002\/acn3.755","article-title":"Alternative splicing in a presenilin 2 variant associated with Alzheimer disease","volume":"6","author":"Braggin","year":"2019","journal-title":"Ann Clin Transl Neurol"},{"key":"2023052502593790800_awac294-B17","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/nrn1387","article-title":"Neurovascular regulation in the normal brain and in Alzheimer\u2019s disease","volume":"5","author":"Iadecola","year":"2004","journal-title":"Nat Rev Neurosci"},{"key":"2023052502593790800_awac294-B18","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1046\/j.1471-4159.1999.0722498.x","article-title":"A novel presenilin-2 splice variant in human Alzheimer\u2019s disease brain tissue","volume":"72","author":"Sato","year":"1999","journal-title":"J Neurochem"},{"key":"2023052502593790800_awac294-B19","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1093\/hmg\/ddv110","article-title":"Alzheimer\u2019s disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of gamma-secretase activity","volume":"24","author":"Moussavi Nik","year":"2015","journal-title":"Hum Mol Genet"},{"key":"2023052502593790800_awac294-B20","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1016\/j.yexcr.2011.04.004","article-title":"The response of HMGA1 to changes in oxygen 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PSEN2","volume":"139","author":"Hsu","year":"2020","journal-title":"Neurobiol Dis"},{"key":"2023052502593790800_awac294-B27","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx Consortium Atlas of genetic regulatory effects across human tissues","volume":"369","author":"GTEx Consortium","year":"2020","journal-title":"Science"},{"key":"2023052502593790800_awac294-B28","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.3233\/JAD-201133","article-title":"Relevance of a truncated PRESENILIN 2 transcript to Alzheimer\u2019s disease and neurodegeneration","volume":"80","author":"Moussavi Nik","year":"2021","journal-title":"J Alzheimers Dis"},{"key":"2023052502593790800_awac294-B29","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.molbrainres.2004.05.019","article-title":"Expression of truncated presenilin 2 splice variant in Alzheimer\u2019s disease, bipolar disorder, and schizophrenia brain 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