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An age at onset\u00a0&lt;\u00a070 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non\u2013right\u2010handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Identifying novel factors enriched in early\u2010onset and non\u2010amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment.<\/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>We identified a suite of novel factors overrepresented in early\u2010onset and non\u2010amnestic AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These factors can be broadly conceptualized as neurodevelopmental (non\u2013right\u2010handedness and learning disability) and neural environmental (seizure and autoimmunity).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70668","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T08:51:50Z","timestamp":1758099110000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Neurodevelopment and neural environment inform Alzheimer's disease age at onset and phenotype"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5991-3053","authenticated-orcid":false,"given":"Zachary A.","family":"Miller","sequence":"first","affiliation":[{"name":"Memory and Aging Center Department of Neurology UCSF Weill Institute for Neurosciences University of California  San Francisco California USA"},{"name":"Dyslexia Center Department of Neurology and Psychiatry UCSF Weill Institute for Neurosciences University of California  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Ossenkoppele","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC  Amsterdam the Netherlands"},{"name":"Clinical Memory Research Unit Sk\u00e5nes universitetssjukhus VE Minnessjukdomar Lund University  Malm\u00f6 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neill R.","family":"Graff\u2010Radford","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel E.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Shwe","sequence":"additional","affiliation":[{"name":"School of Medicine George Washington University  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Department of Medicine Pediatrics University of Colorado  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin J.","family":"Olguin","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Erkkinen","sequence":"additional","affiliation":[{"name":"Department of Neurology Brigham and Women's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. 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