Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia – Nature.com
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2380 Accesses1 Citations449 AltmetricMetrics detailsWe conducted an in-depth longitudinal study on an individual carrying the presenilin 2 p.Asn141Ile mutation, traditionally associated with dominantly inherited Alzheimer’s disease (AD), who has remarkably remained asymptomatic past the expected age of clinical onset. This study combines genetic, neuroimaging and biomarker analyses to explore the underpinnings of this resilience. Unlike typical progression in dominantly inherited AD, tau pathology in this case was confined to the occipital region without evidence of spread, potentially explaining the preservation of cognitive functions. Genetic analysis revealed several variants that, although not previously associated with protection against AD, suggest new avenues for understanding disease resistance. Notably, environmental factors such as significant heat exposure and a unique proteomic profile rich in heat shock proteins might indicate adaptive mechanisms contributing to the observed phenotype. This case underscores the complexity of Alzheimer’s pathology and suggests that blocking tau deposition could be a promising target for therapeutic intervention. The study highlights the need for further research to identify and validate the mechanisms that could inhibit or localize tau pathology as a strategy to mitigate or delay the onset of Alzheimer’s dementia.This is a preview of subscription content, access via your institution
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Download referencesWe acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. Funding information: Data collection and sharing for this project was supported by the Dominantly Inherited Alzheimer Network (grant no. U19AG032438), funded by the National Institute on Aging (NIA), the Alzheimer’s Association (grant no. SG-20-690363-DIAN), the German Center for Neurodegenerative Diseases (DZNE) and the Raul Carrea Institute for Neurological Research (FLENI). Partial support by Research and Development Grants for Dementia from the Japan Agency for Medical Research and Development, AMED grant no. JP22dk0207049, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Spanish Institute of Health Carlos III (ISCIII), Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation and Fonds de Recherche du Québec—Santé.These authors contributed equally: Jorge J. Llibre-Guerra, M. Victoria Fernandez, Nelly Joseph-Mathurin.These authors jointly supervised this work: Carlos Cruchaga, Erik C. B. Johnson, Randall J. Bateman.Washington University in St Louis, St Louis, MO, USAJorge J. Llibre-Guerra, Nelly Joseph-Mathurin, Yan Li, Andrew J. Aschenbrenner, Cyril Pottier, Wendy Sigurdson, Eric McDade, Brian A. Gordon, Tammie L. S. Benzinger, Laura Ibañez, Nico Barthelemy, Matthew Johnson, Jason Hassenstab, Guoqiao Wang, Dan Western, Ciyang Wang, Diana Hobbs, Alisha Daniels, Celeste Karch, John C. Morris, Carlos Cruchaga, Randall J. Bateman, Bryce Baker, Jessica Banks, Nicolas R. Barthélemy, Jamie Bartzel, Randall Bateman, Allison Chen, Charles Chen, Laura Courtney, Alisha J. Daniels, Anne M. Fagan, Shaney Flores, Erin Franklin, Manu Goyal, Emily Gremminger, Cortaiga Hellm, David M. Holtzman, Russ Hornbeck, Laura Ibanez, Kelley Jackson, Gina Jerome, Celeste M. Karch, Sarah Keefe, Deborah Koudelis, Ruijin Lu, Jacob Marsh, Mariana Martin, Parinaz Massoumzadeh, Austin McCullough, Nicole McKay, Matthew Minton, Joyce Nicklaus, Yuzheng Nie, Richard J. Perrin, Christine Pulizos, Jacqueline Rizzo, Edita Sabaredzovic, Jalen Scott, Ashlee Simmons, Karina Skrbec, Jennifer Smith, Jennifer Stauber, Sarah Stout, Charlene Supnet-Bell, Andrei Vlassenko, Qing Wang, Yong Wang, Chengjie Xiong, Xiong Xu, Jinbin Xu, Angela Ziegemeier & Ellen ZiegemeierResearch Center and Memory Clinic, Fundació ACE Institut Català de Neurociències Aplicades – Universitat Internacional de Catalunya (UIC), Barcelona, SpainM. Victoria FernandezEmory University School of Medicine, Atlanta, GA, USAShijia Bian & Kathleen CarterRonald M. Loeb Center for Alzheimer’s Disease, Dept of Genetics and Genomic Sciences, and Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USAAlan E. Renton, Alison M. Goate, Erik C. B. Johnson, Brian Fulton-Howard & Danielle M. PicarelloGrupo de Neurociencias de Antioquia (GNA), Facultad de Medicina, Universidad de Antioquia, Medellín, ColombiaDavid Aguillon, Ana Baena, Yamile Bocanegra, Yudy Milena Leon, Francisco Lopera, Laura Ramirez & Laura SernaInstitute for Neurological Research Fleni, Buenos Aires, ArgentinaRicardo F. Allegri, Patricio Chrem Mendez, Ezequiel Surace & Silvia VazquezNeuroscience Research Australia, Sydney, New South Wales, AustraliaJacob A. Bechara, William S. Brooks, Emma Devenney & Peter R. SchofieldUniversity of Pittsburgh, Pittsburgh, PA, USASarah B. Berman & Snezana IkonomovicDementia Research Centre, UCL Queen Square Institute of Neurology, London, UKDavid M. Cash, Nick C. Fox & Natalie S. RyanMassachusetts General Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USAJasmeer P. Chhatwal & Courtney MaaMayo Clinic in Florida, Jacksonville, FL, USAGregory S. Day & Neill R. Graff-RadfordIndiana University, School of Medicine, Bloomington, IN, USAMartin FarlowGerman Center for Neurodegenerative Diseases (DZNE), Tübingen, GermanySusanne Graber-Sultan, Mathias Jucker, Elke Kuder-Buletta, Christian la Fougère, Christoph Laske, Ulrike Obermueller, Gerald Reischl & Reda TimofejavaiteGoizueta Alzheimer’s Disease Research Center, Emory University, Atlanta, GA, USAEdward D. Huey, Allan I. Levey, Stephen Salloway & Nicholas T. SeyfriedBrain Research Institute, Niigata University, Niigata, JapanTakeshi Ikeuchi, Takanobu Ishiguro & Kensaku KasugaTokyo Metropolitan Institute of Gerontology, Tokyo, JapanKenji IshiiKorea University College of Medicine, Seoul, Republic of South KoreaJae-Hong Lee & Jee Hoon RohGerman Center for Neurodegenerative Diseases, Munich, Munich, GermanyJohannes Levin, Yvonne Rödenbeck & Jonathan VögleinEdith Cowan University, Perth, Western Australia, AustraliaRalph MartinsFlorey Institute, The University of Melbourne, Melbourne, Victoria, AustraliaColin MastersOsaka Metropolitan University, Osaka, JapanHiroshi MoriThe University of Tokyo Hospital, Tokyo, JapanYoshiki NiimiTaub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USAJames M. NobleDepartment of Neurology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USAJohn RingmanMcGill University, Montreal, Quebec, CanadaPedro Rosa-NetoUniversity of Barcelona, Barcelona, SpainRaquel Sanchez-ValleKobe City Medical Center General Hospital, Kobe, JapanMichio SendaYou can also search for this author in
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PubMed Google ScholarJ.J.L.-G. and R.J.B. initiated this work, supervised the study and drafted the manuscript. J.J.L.-G., A.J.A., E.M. and W.S. collected and analyzed the clinical and phenotypic data. N.J.-M., B.A.G., T.L.S.B. and D.H. collected and analyzed the imaging data. M.V.F., C.P., M.J., A.E.R., A.M.G. and C.C. contributed to the genetic analyses and data interpretation. S.B., K.C., M.V.F., D.W., C.W. and E.C.B.J. conducted and analyzed the proteomic studies. L.I., N.B., J.J.L.-G. and R.J.B. assisted with molecular and biomarker data collection and analysis. All authors contributed to reviewing the manuscript and refining data analysis. J.J.L.-G. had direct access to and verified the data reported in the manuscript. J.J.L.-G., M.V.F. and N.J.-M. are first authors and contributed equally. C.C., E.C.B.J. and R.J.B. are senior authors and jointly supervised this work.Correspondence to
Jorge J. Llibre-Guerra or Randall J. Bateman.The authors declare no competing interests.Nature Medicine thanks Yann Le Guen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal, in collaboration with the Nature Medicine team.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Appendix 1: Extended Methods, Appendix 2: Extended Results and Supplementary Figs. 1–11 and Tables 1 and 2.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsLlibre-Guerra, J.J., Fernandez, M.V., Joseph-Mathurin, N. et al. Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia.
Nat Med (2025). https://doi.org/10.1038/s41591-025-03494-0Download citationReceived: 22 July 2024Accepted: 06 January 2025Published: 10 February 2025DOI: https://doi.org/10.1038/s41591-025-03494-0Anyone you share the following link with will be able to read this content:Sorry, a shareable link is not currently available for this article.
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