{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T06:00:15Z","timestamp":1780639215800,"version":"3.54.1"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,5,2]],"date-time":"2021-05-02T00:00:00Z","timestamp":1619913600000},"content-version":"vor","delay-in-days":121,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alz &amp; Dem Diag Ass &amp; Dis Mo"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 (\n                      <jats:italic>PSEN1<\/jats:italic>\n                      ) related familial Alzheimer's disease (AD).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP\u2010related genes. Where\n                      <jats:italic>PSEN1<\/jats:italic>\n                      mutation was identified, brain biopsy was performed. We investigated the link between HSP and AD with PSEN1 in silico pathway analysis and measured\n                      <jats:italic>in vivo<\/jats:italic>\n                      the stability of PSEN1 mutant \u03b3\u2010secretase.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a\n                      <jats:italic>PSEN1<\/jats:italic>\n                      variant (p.Thr291Pro) in an individual presenting with pure SP at 30 years of age. Three years later, SP was associated with severe, fast cognitive decline and amyloid deposition with diffuse cortical plaques on brain biopsy. Biochemical analysis of p.Thr291Pro\n                      <jats:italic>PSEN1<\/jats:italic>\n                      revealed that although the mutation does not alter active \u03b3\u2010secretase reconstitution, it destabilizes \u03b3\u2010secretase\u2010amyloid precursor protein (APP)\/amyloid beta (A\u03b2n) interactions during proteolysis, enhancing the production of longer A\u03b2 peptides. We then extended our analysis to all 226\n                      <jats:italic>PSEN1<\/jats:italic>\n                      pathogenic variants reported and show that 7.5% were associated with pure SP onset followed by cognitive decline later in the disease. We found that\n                      <jats:italic>PSEN1<\/jats:italic>\n                      cases manifesting initially as SP have a later age of onset, are associated with mutations located beyond codon 200, and showed larger diffuse, cored plaques, amyloid\u2010ring arteries, and severe CAA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      We show that pure SP can precede dementia onset in\n                      <jats:italic>PSEN1\u2010<\/jats:italic>\n                      related familial AD. We recommend\n                      <jats:italic>PSEN1<\/jats:italic>\n                      genetic testing in patients presenting with SP with no variants in known HSP\u2010related genes, particularly when associated with a family history of cognitive decline.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/dad2.12186","type":"journal-article","created":{"date-parts":[[2021,5,2]],"date-time":"2021-05-02T07:36:03Z","timestamp":1619940963000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Spastic paraplegia preceding\n                    <i>PSEN1<\/i>\n                    \u2010related familial Alzheimer's disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Viorica","family":"Chelban","sequence":"first","affiliation":[{"name":"Department of\u00a0Neuromuscular Disease, Queen Square Institute of Neurology University College London  London UK"},{"name":"Department of 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