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)

doi:10.1016/S1474-4422(24)00236-9

Observational Study

. 2024 Sep;23(9):913-924.

doi: 10.1016/S1474-4422(24)00236-9. Epub 2024 Jul 26.

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)

Stephanie A Schultz¹, Lei Liu², Aaron P Schultz¹, Colleen D Fitzpatrick¹, Raina Levin¹, Jean-Pierre Bellier², Zahra Shirzadi³, Nelly Joseph-Mathurin⁴, Charles D Chen⁴, Tammie L S Benzinger⁴, Gregory S Day⁵, Martin R Farlow⁶, Brian A Gordon⁴, Jason J Hassenstab⁷, Clifford R Jack Jr⁸, Mathias Jucker⁹, Celeste M Karch¹⁰, Jae-Hong Lee¹¹, Johannes Levin¹², Richard J Perrin¹³, Peter R Schofield¹⁴, Chengjie Xiong¹⁵, Keith A Johnson¹, Eric McDade¹⁶, Randall J Bateman¹⁶, Reisa A Sperling³, Dennis J Selkoe¹⁷, Jasmeer P Chhatwal¹⁸; Dominantly Inherited Alzheimer Network

Collaborators, Affiliations

Collaborators

Dominantly Inherited Alzheimer Network:
David Aguillon, Ricardo F Allegri, Andrew J Aschenbrenner, Bryce Baker, Nicolas Barthelemy, Jacob A Bechara, Sarah B Berman, William S Brooks, David M Cash, Allison Chen, Patricio Chrem Mendez, Laura Courtney, Carlos Cruchaga, Alisha J Daniels, Anne M Fagan, Shaney Flores, Nick C Fox, Erin Franklin, Alison M Goate, Susanne Graber-Sultan, Neill R Graff-Radford, Emily Gremminger, Elizabeth Herries, Anna Hofmann, David M Holtzman, Russ Hornbeck, Edward D Huey, Laura Ibanez, Takeshi Ikeuchi, Snezana Ikonomovic, Kelley Jackson, Steve Jarman, Gina Jerome, Erik C B Johnson, Kensaku Kasuga, Sarah Keefe, Deborah Koudelis, Elke Kuder-Buletta, Christoph Laske, Yudy Milena Leon, Allan I Levey, Yan Li, Jorge J Llibre-Guerra, Francisco Lopera, Ruijin Lu, Jacob Marsh, Ralph Martins, Parinaz Massoumzadeh, Colin Masters, Austin McCullough, Nicole McKay, Matthew Minton, Hiroshi Mori, John C Morris, Neelesh K Nadkarni, Joyce Nicklaus, Yoshiki Niimi, James M Noble, Ulrike Obermueller, Danielle M Picarello, Christine Pulizos, Laura Ramirez, Alan E Renton, John Ringman, Jacqueline Rizzo, Yvonne Roedenbeck, Jee Hoon Roh, Pedro Rosa-Neto, Natalie S Ryan, Edita Sabaredzovic, Stephen Salloway, Raquel Sanchez-Valle, Jalen Scott, Nicholas T Seyfried, Ashlee Simmons, Jennifer Smith, Hunter Smith, Jennifer Stauber, Sarah Stout, Charlene Supnet-Bell, Ezequiel Surace, Silvia Vazquez, Jonathan Vöglein, Guoqiao Wang, Qing Wang, Xiong Xu, Jinbin Xu

Affiliations

¹ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA.
² Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Boston, MA, USA.
³ 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.
⁴ Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.
⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
⁶ Indiana Alzheimer's Disease Research Center, Indianapolis, IN, USA.
⁷ Department of Psychology, Washington University, St Louis, MO, USA.
⁸ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁹ German Center for Neurodegenerative Diseases, Tübingen, Germany.
¹⁰ Department of Psychiatry, Washington University, St Louis, MO, USA.
¹¹ Department of Neurology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.
¹² German Center for Neurodegenerative Diseases, Munich, Germany; Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
¹³ Department of Psychiatry, Washington University, St Louis, MO, USA; Department of Pathology and Immunology, Washington University, St Louis, MO, USA.
¹⁴ Neuroscience Research Australia, Randwick, NSW, Australia; School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia.
¹⁵ Division of Biostatistics, Washington University, St Louis, MO, USA.
¹⁶ Department of Neurology, Washington University, St Louis, MO, USA.
¹⁷ 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.
¹⁸ 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.

PMID: 39074479
PMCID: PMC11822357 (available on 2025-09-01)
DOI: 10.1016/S1474-4422(24)00236-9

Observational Study

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)

Stephanie A Schultz et al. Lancet Neurol. 2024 Sep.

. 2024 Sep;23(9):913-924.

doi: 10.1016/S1474-4422(24)00236-9. Epub 2024 Jul 26.

Authors

Collaborators

Dominantly Inherited Alzheimer Network:
David Aguillon, Ricardo F Allegri, Andrew J Aschenbrenner, Bryce Baker, Nicolas Barthelemy, Jacob A Bechara, Sarah B Berman, William S Brooks, David M Cash, Allison Chen, Patricio Chrem Mendez, Laura Courtney, Carlos Cruchaga, Alisha J Daniels, Anne M Fagan, Shaney Flores, Nick C Fox, Erin Franklin, Alison M Goate, Susanne Graber-Sultan, Neill R Graff-Radford, Emily Gremminger, Elizabeth Herries, Anna Hofmann, David M Holtzman, Russ Hornbeck, Edward D Huey, Laura Ibanez, Takeshi Ikeuchi, Snezana Ikonomovic, Kelley Jackson, Steve Jarman, Gina Jerome, Erik C B Johnson, Kensaku Kasuga, Sarah Keefe, Deborah Koudelis, Elke Kuder-Buletta, Christoph Laske, Yudy Milena Leon, Allan I Levey, Yan Li, Jorge J Llibre-Guerra, Francisco Lopera, Ruijin Lu, Jacob Marsh, Ralph Martins, Parinaz Massoumzadeh, Colin Masters, Austin McCullough, Nicole McKay, Matthew Minton, Hiroshi Mori, John C Morris, Neelesh K Nadkarni, Joyce Nicklaus, Yoshiki Niimi, James M Noble, Ulrike Obermueller, Danielle M Picarello, Christine Pulizos, Laura Ramirez, Alan E Renton, John Ringman, Jacqueline Rizzo, Yvonne Roedenbeck, Jee Hoon Roh, Pedro Rosa-Neto, Natalie S Ryan, Edita Sabaredzovic, Stephen Salloway, Raquel Sanchez-Valle, Jalen Scott, Nicholas T Seyfried, Ashlee Simmons, Jennifer Smith, Hunter Smith, Jennifer Stauber, Sarah Stout, Charlene Supnet-Bell, Ezequiel Surace, Silvia Vazquez, Jonathan Vöglein, Guoqiao Wang, Qing Wang, Xiong Xu, Jinbin Xu

Affiliations

¹ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Medical School, Harvard University, Boston, MA, USA.
² Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Boston, MA, USA.
³ 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.
⁴ Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.
⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
⁶ Indiana Alzheimer's Disease Research Center, Indianapolis, IN, USA.
⁷ Department of Psychology, Washington University, St Louis, MO, USA.
⁸ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁹ German Center for Neurodegenerative Diseases, Tübingen, Germany.
¹⁰ Department of Psychiatry, Washington University, St Louis, MO, USA.
¹¹ Department of Neurology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.
¹² German Center for Neurodegenerative Diseases, Munich, Germany; Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
¹³ Department of Psychiatry, Washington University, St Louis, MO, USA; Department of Pathology and Immunology, Washington University, St Louis, MO, USA.
¹⁴ Neuroscience Research Australia, Randwick, NSW, Australia; School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia.
¹⁵ Division of Biostatistics, Washington University, St Louis, MO, USA.
¹⁶ Department of Neurology, Washington University, St Louis, MO, USA.
¹⁷ 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.
¹⁸ 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.

PMID: 39074479
PMCID: PMC11822357 (available on 2025-09-01)
DOI: 10.1016/S1474-4422(24)00236-9

Abstract

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, [¹¹C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [¹⁸F] fluorodeoxyglucose (FDG)-PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log₁₀ (phosphorylated tau 181), CSF log₁₀ (phosphorylated tau 217), and MRI-based hippocampal volume.

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.

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Conflict of interest statement

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.

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References

1. Ryan NS, Nicholas JM, Weston PSJ, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. The Lancet Neurology 2016; 15: 1326–35. - PubMed
1. Lippa CF, Swearer JM, Kane KJ, et al. Familial Alzheimer’s disease: site of mutation influences clinical phenotype. Ann Neurol 2000; 48: 376–9. - PubMed
1. Lagomarsino VN, Pearse RV, Liu L, et al. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron 2021; 109: 3402–3420.e9. - PMC - PubMed
1. Hsu S, Gordon BA, Hornbeck R, et al. Discovery and validation of autosomal dominant Alzheimer’s disease mutations. Alz Res Therapy 2018; 10: 67. - PMC - PubMed
1. Karch CM, Hernández D, Wang J-C, et al. Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network. Alzheimers Res Ther 2018; 10: 69. - PMC - PubMed

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[1] Ryan NS, Nicholas JM, Weston PSJ, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. The Lancet Neurology 2016; 15: 1326–35. - PubMed

[2] Ryan NS, Nicholas JM, Weston PSJ, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. The Lancet Neurology 2016; 15: 1326–35. - PubMed

[3] Lippa CF, Swearer JM, Kane KJ, et al. Familial Alzheimer’s disease: site of mutation influences clinical phenotype. Ann Neurol 2000; 48: 376–9. - PubMed

[4] Lippa CF, Swearer JM, Kane KJ, et al. Familial Alzheimer’s disease: site of mutation influences clinical phenotype. Ann Neurol 2000; 48: 376–9. - PubMed

[5] Lagomarsino VN, Pearse RV, Liu L, et al. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron 2021; 109: 3402–3420.e9. - PMC - PubMed

[6] Lagomarsino VN, Pearse RV, Liu L, et al. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron 2021; 109: 3402–3420.e9. - PMC - PubMed

[7] Hsu S, Gordon BA, Hornbeck R, et al. Discovery and validation of autosomal dominant Alzheimer’s disease mutations. Alz Res Therapy 2018; 10: 67. - PMC - PubMed

[8] Hsu S, Gordon BA, Hornbeck R, et al. Discovery and validation of autosomal dominant Alzheimer’s disease mutations. Alz Res Therapy 2018; 10: 67. - PMC - PubMed

[9] Karch CM, Hernández D, Wang J-C, et al. Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network. Alzheimers Res Ther 2018; 10: 69. - PMC - PubMed

[10] Karch CM, Hernández D, Wang J-C, et al. Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network. Alzheimers Res Ther 2018; 10: 69. - PMC - PubMed

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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)

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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)

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