Jasmeer P Chhatwal1, Stephanie A Schultz2, Eric McDade3, Aaron P Schultz2, Lei Liu4, Bernard J Hanseeuw5, Nelly Joseph-Mathurin6, Rebecca Feldman6, Colleen D Fitzpatrick7, Kathryn P Sparks8, Johannes Levin9, Sarah B Berman10, Alan E Renton11, Bianca T Esposito11, Maria Vitoria Fernandez12, Yun Ju Sung12, Jae Hong Lee13, William E Klunk14, Anna Hofmann15, James M Noble16, Neill Graff-Radford17, Hiroshi Mori18, Steven M Salloway19, Colin L Masters20, Ralph Martins21, Celeste M Karch3, Chengjie Xiong22, Carlos Cruchaga12, Richard J Perrin23, Brian A Gordon6, Tammie L S Benzinger6, Nick C Fox24, Peter R Schofield25, Anne M Fagan3, Alison M Goate11, John C Morris3, Randall J Bateman3, Keith A Johnson26, Reisa A Sperling26. 1. Department of Neurology, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA. Electronic address: chhatwal.jasmeer@mgh.harvard.edu. 2. Department of Neurology, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA. 3. Department of Neurology, Washington University in St Louis, St Louis, MO, USA. 4. Department of Neurology, Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA. 5. Department of Neurology, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Université Catholique de Louvain, Brussels, Belgium. 6. Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, MO, USA. 7. Massachusetts General Hospital, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA. 8. Massachusetts General Hospital, Boston, MA, USA. 9. Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany. 10. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. 11. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 12. Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA. 13. Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 14. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. 15. German Center for Neurodegenerative Disease, Tübingen, Germany. 16. Columbia University Irving Medical Center, Department of Neurology, New York, NY, USA. 17. Mayo Clinic, Department of Neurology, Jacksonville, FL, USA. 18. Osaka City University, Sumiyoshi Ward, Osaka, Japan. 19. Butler Hospital, Memory and Aging Program, Brown University Alpert Medical School, Providence, RI, USA. 20. The University of Melbourne, Melbourne, VIC, Australia; Florey Institute, Melbourne, VIC, Australia. 21. Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australia. 22. Division of Biostatistics, Washington University in St Louis, St Louis, MO, USA. 23. Department of Pathology, Washington University in St Louis, St Louis, MO, USA. 24. UCL Queen Square Institute of Neurology, Dementia Research Centre, London, UK. 25. Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. 26. Department of Neurology, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA.
Abstract
BACKGROUND: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP. METHODS: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40). FINDINGS: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses. INTERPRETATION: Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes. FUNDING: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development.
BACKGROUND: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP. METHODS: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40). FINDINGS: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses. INTERPRETATION: Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes. FUNDING: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development.
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