γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).
| Autor: | Schultz SA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA., Liu L; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Boston, MA, USA., Schultz AP; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA., Fitzpatrick CD; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA., Levin R; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA., Bellier JP; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Boston, MA, USA., Shirzadi Z; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA., Joseph-Mathurin N; Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA., Chen CD; Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA., Benzinger TLS; Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA., Day GS; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA., Farlow MR; Indiana Alzheimer's Disease Research Center, Indianapolis, IN, USA., Gordon BA; Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA., Hassenstab JJ; Department of Psychology, Washington University, St Louis, MO, USA., Jack CR Jr; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Jucker M; German Center for Neurodegenerative Diseases, Tübingen, Germany., Karch CM; Department of Psychiatry, Washington University, St Louis, MO, USA., Lee JH; Department of Neurology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea., Levin J; German Center for Neurodegenerative Diseases, Munich, Germany; Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany., Perrin RJ; Department of Psychiatry, Washington University, St Louis, MO, USA; Department of Pathology and Immunology, Washington University, St Louis, MO, USA., Schofield PR; Neuroscience Research Australia, Randwick, NSW, Australia; School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia., Xiong C; Division of Biostatistics, Washington University, St Louis, MO, USA., Johnson KA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA., McDade E; Department of Neurology, Washington University, St Louis, MO, USA., Bateman RJ; Department of Neurology, Washington University, St Louis, MO, USA., Sperling RA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA., Selkoe DJ; Department of Neurology, Medical School, Harvard University, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Boston, MA, USA., Chhatwal JP; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Boston, MA, USA. Electronic address: chhatwal.jasmeer@mgh.harvard.edu. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | The Lancet. Neurology [Lancet Neurol] 2024 Sep; Vol. 23 (9), pp. 913-924. Date of Electronic Publication: 2024 Jul 26. |
| DOI: | 10.1016/S1474-4422(24)00236-9 |
| Abstrakt: | Background: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production. Methods: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [ 11 C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [ 18 F] fluorodeoxyglucose (FDG)-PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log Findings: Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p<0·0001). GSC was associated with MMSE (β=0·08, SE 0·03; p=0·0043), CDR-SB (-0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB-PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). Interpretation: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. Funding: US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III. Competing Interests: Declaration of interests SAS receives research funding from the Alzheimer's Association and the US National Institutes of Health (NIH). LL receives research funding from the US NIH; consulting fees from Korro Bio; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Biogen and Cell Signaling Technology. NJ-M receives research funding from the Alzheimer's Association and the US NIH. RJB receives research funding from the US NIH, Biogen, AbbVie, Bristol Myers Squibb, Novartis, the US National Intelligence Authority, US National Institute of Neurological Disorders and Stroke, Centene, the Rainwater Foundation, the BrightFocus Foundation, the Association for Frontotemporal Degeneration Biomarkers Initiative, Coins for Alzheimer's Research Trust Fund, the Good Ventures Foundation, Hoffman–La Roche, CogState, Signant, the Cure Alzheimer's Research Trust Fund, Eisai, and C2N Diagnostics; receives royalties or licences from C2N Diagnosticsf payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the Korean Dementia Association, the American Neurological Association, Fondazione Prada, Weill Cornell Medical College, Harvard University, Beeson, and Adler Symposium. ZS receives research funding from the BrightFocus Foundation, the Foundation for Barnes-Jewish Hospital, Eli Lilly, the Health Equity Scholars Program, and the Alzheimer's Society of Canada. RAS receives research funding from the US NIH, the Gerald and Henrietta Rauenhorst Foundation, Eli Lilly, the Alzheimer's Assocation, and Eisai and receives consulting fees from AbbVie, Bristol Myers Squibb, Eisai, Eli Lilly, Roche, Prothena, AC Immune, Acumen, Alector, Alnylam, Biohaven, Genentech, Janssen, the Japanese Organization for Medical Device Development, Nervgen, Neuraly, Neurocentria, Oligomerix, Renew, Shionogi, Vigil Neuroscience, Ionis, and Vaxxinity. GSD receives research funcing from the US NIH, the Alzheimer's Association, and the Chan–Zuckerberg Initiative; consulting fees from Parabon Nanolabs and Arialysis Therapeutics; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from PeerView Media, Continuing Education, Eli Lilly, DynaMed, and SixSense Concierge. EM receives research funding from the US National Intelligence Authority, Eisai, Eli Lilly, Roche, and the Gerald and Henrietta Rauenhorst Foundation; consulting fees from AstraZeneca, Sanofi, and Merck; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the Alzheimer Association, Projects in Knowledge, and Neurology Live. JPC receives research funding from the US NIH. RJP receives grants from the US NIH. JL is a consultant for and receives grants, contracts, and royalties from Eisai, Eli Lilly, the German Center of Neurodegenerative Diseases, the German Ministry for Research and Education, the Anton and Petra Ehrmann Foundation, the Luneburg Foundation, Innovationsfonds, the Michael J Fox Foundation, CurePSP, the Jerome LeJeune Foundation, the Alzheimer Forschungs Initiative, Deutsche Stiftung Down Syndrom, Else Kroner Fresenius Stiftung, and MODAG. DJS receives consulting fees from Prothena Biosciences and Eisai. CX receives research funding from the US NIH and consulting fees from Diadem. PRS receives research funding from the the US NIH, the Roth Charitable Foundation, the Australian National Health and Medical Research Council, and the Australian Medical Research Future Fund and receives consulting fees from Outside Opinion and Moira Clay Consulting. JJL receives research funding from the German Center for Neurodegenerative Diseases, the German Ministry for Research and Education, the Anton and Petra Ehrmann Foundation, the Lüneburg Foundation, Innovationsfonds, the Michael J Fox Foundation for Parkinson's Research, CurePSP, the Jerome LeJeune Foundation, the Alzheimer Forschungs Initiative, Deutsche Stiftung Down Syndrom, and Else Kröner Fresenius Stiftung; consulting fees from Eisai and Biogen; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer Vital, Biogen, Eisai, Teva, Roche, and Zambon. MJ receives payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Eisai. TLSB receives research funding from the US NIH and Siemens; consulting fees from Biogen, Eli Lilly, Eisai, Bristol Myers Squibb, and Johnson & Johnson; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Medscape and PeerView. All other authors declare no competing interests. (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|