Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease.

Autor: Schultz SA; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Shirzadi Z; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Schultz AP; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Liu L; Brigham and Women's Hospital, Boston, Massachusetts, USA.; Ann Romney Center for Neurologic Diseases, Boston, Massachusetts, USA., Fitzpatrick CD; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., McDade E; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Barthelemy NR; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Renton A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Esposito B; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Joseph-Mathurin N; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Cruchaga C; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Chen CD; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Goate A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Allegri RF; INEBA, Buenos Aires, Argentina., Benzinger TLS; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Berman S; University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Chui HC; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Fagan AM; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Farlow MR; Indiana Alzheimer's Disease Research Center, Indianapolis, Indiana, USA., Fox NC; Dementia Research Centre & UK Dementia Research Institute, UCL Institute of Neurology, London, UK., Gordon BA; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Day GS; Mayo Clinic, Jacksonville, Florida, USA., Graff-Radford NR; Mayo Clinic, Jacksonville, Florida, USA., Hassenstab JJ; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Hanseeuw BJ; Institute of Neuroscience, UCLouvain, Brussels, Belgium.; Gordon Center for Medical Imaging in the Radiology Department of MGH, Boston, Massachusetts, USA., Hofmann A; German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany., Jack CR Jr; Mayo Clinic, Rochester, Minnesota, USA., Jucker M; German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany., Karch CM; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Koeppe RA; University of Michigan, Ann Arbor, Michigan, USA., Lee JH; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Levey AI; Emory Goizueta Alzheimer's Disease Research Center, Atlanta, Georgia, USA., Levin J; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Martins RN; Edith Cowan University, Joondalup, Western Australia, Australia., Mori H; Osaka City University Medical School, Osaka, Japan., Morris JC; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Noble J; Columbia University, New York, New York, USA., Perrin RJ; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Rosa-Neto P; Translational Neuroimaging Laboratory, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada., Salloway SP; Butler Hospital, Providence, Rhode Island, USA., Sanchez-Valle R; Alzheimer's disease and other cognitive disorders Unit, Neurology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomediques, Barcelona, Spain., Schofield PR; Neuroscience Research Australia, Randwick, New South Wales, Australia.; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia., Xiong C; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Johnson KA; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Brigham and Women's Hospital, Boston, Massachusetts, USA., Bateman RJ; Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Sperling RA; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Brigham and Women's Hospital, Boston, Massachusetts, USA., Chhatwal JP; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Brigham and Women's Hospital, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2023 Aug; Vol. 22 (8), pp. e13871. Date of Electronic Publication: 2023 Jun 08.
DOI: 10.1111/acel.13871
Abstrakt: Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.
(© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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