Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer's disease.

Autor:	Llibre-Guerra JJ; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA., Iaccarino L; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Coble D; Division of Biostatistics, Washington University in St Louis, St Louis, MO 63108, USA., Edwards L; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Li Y; Division of Biostatistics, Washington University in St Louis, St Louis, MO 63108, USA., McDade E; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA., Strom A; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Gordon B; Malinckrodt Institute of Radiology, Washington University in St Louis, St Louis, MO 63108, USA., Mundada N; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Schindler SE; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA., Tsoy E; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Ma Y; Division of Biostatistics, Washington University in St Louis, St Louis, MO 63108, USA., Lu R; Division of Biostatistics, Washington University in St Louis, St Louis, MO 63108, USA., Fagan AM; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA., Benzinger TLS; Malinckrodt Institute of Radiology, Washington University in St Louis, St Louis, MO 63108, USA., Soleimani-Meigooni D; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Aschenbrenner AJ; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA., Miller Z; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Wang G; Division of Biostatistics, Washington University in St Louis, St Louis, MO 63108, USA., Kramer JH; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Hassenstab J; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA., Rosen HJ; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Morris JC; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA., Miller BL; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Xiong C; Division of Biostatistics, Washington University in St Louis, St Louis, MO 63108, USA., Perrin RJ; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA.; Department of Pathology and Immunology, Washington University in St Louis, St. Louis, MO 63108, USA., Allegri R; Department of Cognitive Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina., Chrem P; Department of Cognitive Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina., Surace E; Department of Cognitive Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina., Berman SB; Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA., Chhatwal J; Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Masters CL; Florey Institute, The University of Melbourne, Melbourne 3052, Australia., Farlow MR; Neuroscience Center, Indiana University School of Medicine at Indianapolis, IN 46202, USA., Jucker M; DZNE-German Center for Neurodegenerative Diseases, Tübingen 72076, Germany.; Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany., Levin J; Department of Neurology, Ludwig-Maximilians-University, Munich 80539, Germany.; German Center for Neurodegenerative Diseases, Munich 81377, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich 81377, Germany., Fox NC; Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London WC1N 3BG, UK., Day G; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL 33224, USA., Gorno-Tempini ML; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Boxer AL; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., La Joie R; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA., Rabinovici GD; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, USA., Bateman R; Department of Neurology, Washington University in St Louis, St Louis, MO 63108, USA.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2023 Oct 18; Vol. 5 (6), pp. fcad280. Date of Electronic Publication: 2023 Oct 18 (Print Publication: 2023).
DOI:	10.1093/braincomms/fcad280
Abstrakt:	Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t -tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline ( P = 0.006) and 46.1% versus 25.4% at last visit ( P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency ( P < 0.001), Trail Making Test Part B ( P < 0.001) and digit span ( P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points ( P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels ( P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design. Competing Interests: J.J.L.-G.’s research is supported by NIH-NIA (K01AG073526), the Alzheimer’s Association (AARFD-21-851415 and SG-20-690363), the Michael J. Fox Foundation (MJFF-020770), the Foundation for Barnes-Jewish Hospital and the McDonnell Academy. A.M.F., PhD, is the Biomarker Core Leader of the DIAN-TU. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR and Otsuka Pharmaceuticals. T.L.S.B., MD, PhD, has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. T.L.S.B. participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen and F. Hoffmann-La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker’s Bureau for Biogen. J.C.M., MD, is the Friedman Distinguished Professor of Neurology, Director, Knight ADRC, Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444, P01AG003991, P01AG026276, U19 AG032438 and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. A.J.A., PhD, has served as a consultant for Biogen Inc and H. Lundbeck HS. J.H., PhD, is a paid consultant for F. Hoffmann-La Roche, Ltd., Takeda, and Lundbeck and is on the Data Safety and Monitoring Board for Eisai. J.L., MD, reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen and author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH and is an inventor in a patent ‘Pharmaceutical Composition and Methods of Use’ (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. L.I. is currently a full-time employee of Eli Lilly and Company/Avid Radiopharmaceuticals and a minor shareholder of Eli Lilly and Company. His contribution to the work presented in this manuscript was performed while he was affiliated with the University of California San Francisco. G.D.R., MD, receives research support from NIA P30-AG062422, U01-AG057195, R35 AG072362, R56-AG075744, NINDS R21-NS120629, Alzheimer’s Association ZEN-21-848216, American College of Radiology, Rainwater Charitable Foundation, Shenandoah Foundation, Avid Radiopharmaceuticals, Life Molecular Imaging, GE Healthcare and Genentech. He has served as a consultant for Alector, Eli Lilly, Genentech, GE Healthcare, Roche, Johnson & Johnson and Merck. He serves as associate editor for JAMA Neurology. All other authors report no conflict of interest relevant to this manuscript. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu