{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:38:08Z","timestamp":1791279488442,"version":"4.1.0"},"reference-count":45,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T00:00:00Z","timestamp":1480291200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2017,1,12]]},"abstract":"<jats:p>Background: The major genetic risk factor for late onset Alzheimer\u2019s disease (AD) is the APOE- \u025b4 allele. However, APOE- \u025b4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants.<\/jats:p>\n                  <jats:p>Objective: To identify genetic factors that, next to APOE- \u025b4 homozygosity, contribute to the development of AD.<\/jats:p>\n                  <jats:p>Methods: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members.<\/jats:p>\n                  <jats:p>Results: All affected family members were homozygous for the APOE- \u025b4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE- \u025b4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with A\u03b2PP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with A\u03b2PP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds\/cerebral amyloid angiopathy and electroencephalographic abnormalities.<\/jats:p>\n                  <jats:p>Conclusion: We hypothesize that next to APOE- \u025b4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed A\u03b2 processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.<\/jats:p>","DOI":"10.3233\/jad-160091","type":"journal-article","created":{"date-parts":[[2016,11,29]],"date-time":"2016-11-29T11:40:32Z","timestamp":1480419632000},"page":"63-74","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":40,"title":["Rare Genetic Variant in\n                    <i>SORL1<\/i>\n                    May Increase Penetrance of Alzheimer\u2019s Disease in a Family with Several Generations of\n                    <i>APOE<\/i>\n                    -\n                    <i>\u025b<\/i>\n                    4 Homozygosity"],"prefix":"10.1177","volume":"56","author":[{"given":"Eva","family":"Louwersheimer","sequence":"first","affiliation":[{"name":"Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra E.","family":"Cohn-Hokke","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolande A.L.","family":"Pijnenburg","sequence":"additional","affiliation":[{"name":"Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjan M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik A.","family":"Sistermans","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke J.","family":"Rozemuller","sequence":"additional","affiliation":[{"name":"Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Hulsman","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands"},{"name":"Delft Bioinformatics Laboratory, Delft University of Technology, Delft, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"van Swieten","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands"},{"name":"Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cock M.","family":"van Duijn","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands"},{"name":"Institutes of Neurology and Healthcare Engineering, UCL, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teddy","family":"Koene","sequence":"additional","affiliation":[{"name":"Alzheimer Center & Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Scheltens","sequence":"additional","affiliation":[{"name":"Alzheimer Center and 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