{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:48:24Z","timestamp":1783529304036,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,6,2]],"date-time":"2024-06-02T00:00:00Z","timestamp":1717286400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017510","name":"UK Dementia Research Institute","doi-asserted-by":"publisher","award":["UKDRI\u20101014"],"award-info":[{"award-number":["UKDRI\u20101014"]}],"id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M02492X\/1"],"award-info":[{"award-number":["MR\/M02492X\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Familial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      To determine the pathogenicity of the unclassified\n                      <jats:italic>PSEN1<\/jats:italic>\n                      P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient\u2010derived induced pluripotent stem cell (iPSC) models (two donors), and post\u2010mortem histology (one donor).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>An autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and post\u2010mortem tissue supported high production of amyloid beta 43 (A\u03b243). PSEN1 peptide maturation was unimpaired.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      We confirm that the P436S mutation in\n                      <jats:italic>PSEN1<\/jats:italic>\n                      causes atypical fAD. The location of the mutation in the critical PSEN1 proline\u2010alanine\u2010leucine\u2010proline (PALP) motif may explain the early age at onset despite appropriate protein maturation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>PSEN1<\/jats:italic>\n                            P436S mutations cause familial Alzheimer's disease.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This mutation is associated with atypical clinical presentation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Induced pluripotent stem cells (iPSCs) and post\u2010mortem studies support increased amyloid beta (A\u03b243) production.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Early age at onset highlights the importance of the PALP motif in PSEN1 function.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.13904","type":"journal-article","created":{"date-parts":[[2024,6,2]],"date-time":"2024-06-02T08:04:10Z","timestamp":1717315450000},"page":"4717-4726","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated A\u03b243 and atypical clinical manifestations"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9743-8134","authenticated-orcid":false,"given":"Charles","family":"Arber","sequence":"first","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R. S.","family":"Belder","sequence":"additional","affiliation":[{"name":"Dementia Research Centre UCL Queen Square Institute of Neurology  London UK"},{"name":"UCL Queen Square Institute of Neurology UK Dementia Research Institute at UCL  London UK"},{"name":"Adelaide Medical School The University of Adelaide  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Tomczuk","sequence":"additional","affiliation":[{"name":"Department of Genetics Institute of Psychiatry and Neurology  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Gabriele","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazead","family":"Buhidma","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00edona","family":"Farrell","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology  London UK"},{"name":"UCL Queen Square Institute of Neurology UK Dementia Research Institute at UCL  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoinette","family":"O'Connor","sequence":"additional","affiliation":[{"name":"Dementia Research Centre UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Rice","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology  London UK"},{"name":"Dementia Research Centre UCL Queen Square Institute of Neurology  London UK"},{"name":"UCL Queen Square Institute of Neurology UK Dementia Research Institute at UCL  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammaryn","family":"Lashley","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick C.","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology  London UK"},{"name":"Dementia Research Centre UCL Queen Square Institute of Neurology  London UK"},{"name":"UCL Queen Square Institute of Neurology UK Dementia Research Institute at UCL  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie S.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology  London UK"},{"name":"Dementia Research Centre UCL Queen Square Institute of Neurology  London UK"},{"name":"UCL Queen Square 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