Research Contributions

For more than 20 years, the Fagan lab at Washington University in St. Louis (WUSTL) has studied Alzheimer disease (AD), with a particular focus on the role of fluid-based biomarkers and their utility as diagnostic and prognostic disease markers, notably during the preclinical/asymptomatic stage. Some of our major discoveries, research goals and a summary list of publications are highlighted below. A comprehensive list of lab publications can be found here.

CSF biomarkers are useful for identifying underlying AD pathology. Although CSF Aβ42 and tau have been extensively studied, their relationships with underlying disease processes are still poorly understood. Studies evaluating the relationships between traditional CSF biomarkers and underlying disease processes require longitudinal evaluation of fluid biomarkers with other biomarker modalities (e.g., amyloid/tau positron emission tomography [PET], fluorodeoxyglucose [FDG] PET, structural magnetic resonance imaging [MRI], etc.) within individuals as they progress through the natural course of the disease.1–7 In collaboration with colleagues at the Knight ADRC and the University of Pittsburgh, the Fagan lab was the first to demonstrate that a low level of CSF Aβ42 is an indicator of cortical amyloid deposition via PET even during the asymptomatic/preclinical period.8–15 Our more recent work in collaboration with the Bateman lab at WUSTL supports the potential utility of plasma Aβ levels for similarly identifying underlying brain amyloidosis.16 We also demonstrated relationships between CSF measures of phosphorylated tau-related processes and neuronal injury with brain volumetric measures and tau PET8,14,17,18. These data are crucial for ultimately validating the use of CSF markers for disease diagnosis, staging, prognosis and demonstrating eventual therapeutic efficacy. CSF biomarkers are already being used in the first ever secondary prevention trial in autosomal-dominant AD (Dominantly Inherited Alzheimer Network Trials Unit [DIAN TU]) as indices of target engagement, as well as effects on downstream pathology (NCT01760005, www.clinicaltrials.gov).

CSF biomarkers are useful for staging individuals during the preclinical period. The concept of AD as a long, progressive disease that begins several decades prior to the onset of clinical symptoms was facilitated by the development of fluid and imaging biomarkers. This conceptualization has prompted diagnostic criteria that include biomarker results. By definition, biomarkers are required for identifying individuals in the preclinical (asymptomatic) period. Our work in biomarkers of preclinical AD (in individuals at risk for both late-onset and autosomal dominant forms) was instrumental in the crafting/validation of these proposed stages1,2,4,6,8,12,18–23. Such findings are now informing the design and evaluation of prevention trials in AD1,19,24.

CSF biomarkers are useful for predicting future cognitive decline in early and pre-symptomatic stages. The critical element required for establishing biomarker validity and utility in early disease stages is its ability to predict future dementia. Furthermore, knowledge of when a person in the preclinical stage is likely to develop dementia symptoms will be efficacious for clinical trial design in shortening trial duration and reducing cost. The Fagan lab and our colleagues have demonstrated the utility of CSF biomarkers (notably the total tau/Aβ42 and phosphorylated tau/Aβ42 ratios) to predict which individuals will develop cognitive abnormalities14,18,21,25,26.

Novel biomarkers are necessary to determine the state of other neuropathologic processes in AD. Despite the utility of established CSF analytes (Aβ42, tau, ptau) for identifying core AD pathologies and predicting cognitive decline, there still remains a need for markers of additional pathogenic processes (e.g., neuroinflammation and synaptic/neuronal stress and dysfunction) in both AD and non-AD neuropathologic processes. The Fagan lab and colleagues have published several studies describing novel markers of neuronal injury and neuroinflammation, such as visinin-like protein 1 (VILIP-1), neurogranin (Ng), synaptosomal-associated protein 25 (SNAP-25), soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) and chitinase 3-like protein 1 (YKL-40)1,3,6,16,22,27–31. Levels of these markers differ among clinical groups and, when combined with markers of amyloid, predict future cognitive decline25,26,30,32.

Bringing validated biomarkers to clinical practice requires global biomarker standardization efforts. Although CSF biomarkers exhibit excellent diagnostic and prognostic utility when used in research settings, their potential use for individual patient care is limited by inconsistent protocols for sample collection and processing and demonstrated variability in current assay performance. To address these inadequacies, high-level AD research and clinical labs are formally investigating within- and between-lab sources of assay variability10,33,34. In collaboration with investigators at WUSTL and other US and international research labs, the Fagan lab has contributed to these standardization efforts. Our engagement in these efforts is furthered by ongoing participation in discussions and meetings sponsored by AD working groups of the Coalition Against Major Diseases (CAMD), Collaboration for Alzheimer’s Prevention (CAP) and the Global Biomarker Standardization Consortium (GBSD).

Selected Publications

  1. Fagan, Anne M., Chengjie Xiong, Mateusz S. Jasielec, Randall J. Bateman, Alison M. Goate, Tammie L. S. Benzinger, Bernardino Ghetti, Ralph N. Martins, Colin L. Masters, Richard Mayeux, John M. Ringman, Martin N. Rossor, Stephen Salloway, Peter R. Schofield, Reisa A. Sperling, Daniel Marcus, Nigel J. Cairns, Virginia D. Buckles, Jack H. Ladenson, John C. Morris, David M. Holtzman, and Dominantly Inherited Alzheimer Network. 2014. “Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease.” Science Translational Medicine 6(226):226ra30. doi: 10.1126/scitranslmed.3007901.

  2. Sutphen, Courtney L., Mateusz S. Jasielec, Aarti R. Shah, Elizabeth M. Macy, Chengjie Xiong, Andrei G. Vlassenko, Tammie L. S. Benzinger, Erik E. J. Stoops, Hugo M. J. Vanderstichele, Britta Brix, Heather D. Darby, Manu L. J. Vandijck, Jack H. Ladenson, John C. Morris, David M. Holtzman, and Anne M. Fagan. 2015. “Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age.” JAMA Neurology 72(9):1029–42. doi: 10.1001/jamaneurol.2015.1285.

  3. Sutphen, Courtney L., Lena McCue, Elizabeth M. Herries, Chengjie Xiong, Jack H. Ladenson, David M. Holtzman, Anne M. Fagan, and ADNI. 2018. “Longitudinal Decreases in Multiple Cerebrospinal Fluid Biomarkers of Neuronal Injury in Symptomatic Late Onset Alzheimer’s Disease.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 14(7):869–79. doi: 10.1016/j.jalz.2018.01.012.

  4. Llibre-Guerra, Jorge J., Yan Li, Suzanne E. Schindler, Brian A. Gordon, Anne M. Fagan, John C. Morris, Tammie L. S. Benzinger, Jason Hassenstab, Guoqiao Wang, Ricardo Allegri, Sarah B. Berman, Jasmeer Chhatwal, Martin R. Farlow, David M. Holtzman, Mathias Jucker, Johannes Levin, James M. Noble, Stephen Salloway, Peter Schofield, Celeste Karch, Nick C. Fox, Chengjie Xiong, Randall J. Bateman, and Eric McDade. 2019. “Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease.” JAMA Network Open 2(12):e1917126. doi: 10.1001/jamanetworkopen.2019.17126.

  5. McDade, Eric, Guoqiao Wang, Brian A. Gordon, Jason Hassenstab, Tammie L. S. Benzinger, Virginia Buckles, Anne M. Fagan, David M. Holtzman, Nigel J. Cairns, Alison M. Goate, Daniel S. Marcus, John C. Morris, Katrina Paumier, Chengjie Xiong, Ricardo Allegri, Sarah B. Berman, William Klunk, James Noble, John Ringman, Bernardino Ghetti, Martin Farlow, Reisa A. Sperling, Jasmeer Chhatwal, Stephen Salloway, Neill R. Graff-Radford, Peter R. Schofield, Colin Masters, Martin N. Rossor, Nick C. Fox, Johannes Levin, Mathias Jucker, Randall J. Bateman, and Dominantly Inherited Alzheimer Network. 2018. “Longitudinal Cognitive and Biomarker Changes in Dominantly Inherited Alzheimer Disease.” Neurology 91(14):e1295–1306. doi: 10.1212/WNL.0000000000006277.

  6. Vos, Stephanie Jb, Chengjie Xiong, Pieter Jelle Visser, Mateusz S. Jasielec, Jason Hassenstab, Elizabeth A. Grant, Nigel J. Cairns, John C. Morris, David M. Holtzman, and Anne M. Fagan. 2013. “Preclinical Alzheimer’s Disease and Its Outcome: A Longitudinal Cohort Study.” The Lancet. Neurology 12(10):957–65. doi: 10.1016/S1474-4422(13)70194-7.

  7. Xiong, Chengjie, Mateusz S. Jasielec, Hua Weng, Anne M. Fagan, Tammie L. S. Benzinger, Denise Head, Jason Hassenstab, Elizabeth Grant, Courtney L. Sutphen, Virginia Buckles, Krista L. Moulder, and John C. Morris. 2016. “Longitudinal Relationships among Biomarkers for Alzheimer Disease in the Adult Children Study.” Neurology 86(16):1499–1506. doi: 10.1212/WNL.0000000000002593.

  8. Fagan, Anne M., Denise Head, Aarti R. Shah, Daniel Marcus, Mark Mintun, John C. Morris, and David M. Holtzman. 2009. “Decreased CSF Aβ42 Correlates with Brain Atrophy in Cognitively Normal Elderly.” Annals of Neurology 65(2):176–83. doi: 10.1002/ana.21559.

  9. Fagan, Anne M., Mark A. Mintun, Robert H. Mach, Sang-Yoon Lee, Carmen S. Dence, Aarti R. Shah, Gina N. LaRossa, Michael L. Spinner, William E. Klunk, Chester A. Mathis, Steven T. DeKosky, John C. Morris, and David M. Holtzman. 2006. “Inverse Relation between in Vivo Amyloid Imaging Load and Cerebrospinal Fluid Abeta42 in Humans.” Annals of Neurology 59(3):512–19. doi: 10.1002/ana.20730.

  10. Fagan, Anne M., Leslie M. Shaw, Chengjie Xiong, Hugo Vanderstichele, Mark A. Mintun, John Q. Trojanowski, Els Coart, John C. Morris, and David M. Holtzman. 2011. “Comparison of Analytical Platforms for Cerebrospinal Fluid Measures of β-Amyloid 1-42, Total Tau, and p-Tau181 for Identifying Alzheimer Disease Amyloid Plaque Pathology.” Archives of Neurology 68(9):1137–44. doi: 10.1001/archneurol.2011.105.

  11. Schindler, Suzanne E., Julia D. Gray, Brian A. Gordon, Chengjie Xiong, Richard Batrla-Utermann, Marian Quan, Simone Wahl, Tammie L. S. Benzinger, David M. Holtzman, John C. Morris, and Anne M. Fagan. 2018. “Cerebrospinal Fluid Biomarkers Measured by Elecsys Assays Compared to Amyloid Imaging.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 14(11):1460–69. doi: 10.1016/j.jalz.2018.01.013.

  12. Vlassenko, Andrei G., Lena McCue, Mateusz S. Jasielec, Yi Su, Brian A. Gordon, Chengjie Xiong, David M. Holtzman, Tammie L. S. Benzinger, John C. Morris, and Anne M. Fagan. 2016. “Imaging and Cerebrospinal Fluid Biomarkers in Early Preclinical Alzheimer Disease.” Annals of Neurology 80(3):379–87. doi: 10.1002/ana.24719.

  13. Lewczuk, Piotr, Anja Matzen, Kaj Blennow, Lucilla Parnetti, Jose Luis Molinuevo, Paolo Eusebi, Johannes Kornhuber, John C. Morris, and Anne M. Fagan. n.d. “Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer’s Disease.” Journal of Alzheimer’s Disease 55(2):813–22. doi: 10.3233/JAD-160722.

  14. Brier, Matthew R., Brian Gordon, Karl Friedrichsen, John McCarthy, Ari Stern, Jon Christensen, Christopher Owen, Patricia Aldea, Yi Su, Jason Hassenstab, Nigel J. Cairns, David M. Holtzman, Anne M. Fagan, John C. Morris, Tammie L. S. Benzinger, and Beau M. Ances. 2016. “Tau and Aβ Imaging, CSF Measures, and Cognition in Alzheimer’s Disease.” Science Translational Medicine 8(338):338ra66. doi: 10.1126/scitranslmed.aaf2362.

  15. Kaplow, June, Manu Vandijck, Julia Gray, Michio Kanekiyo, Els Huyck, C. J. Traynham, Rianne Esquivel, Anne M. Fagan, and Johan Luthman. 2020. “Concordance of Lumipulse Cerebrospinal Fluid T-Tau/Aβ42 Ratio with Amyloid PET Status.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 16(1):144–52. doi: 10.1002/alz.12000.

  16. Schindler, Suzanne E., James G. Bollinger, Vitaliy Ovod, Kwasi G. Mawuenyega, Yan Li, Brian A. Gordon, David M. Holtzman, John C. Morris, Tammie L. S. Benzinger, Chengjie Xiong, Anne M. Fagan, and Randall J. Bateman. 2019. “High-Precision Plasma β-Amyloid 42/40 Predicts Current and Future Brain Amyloidosis.” Neurology 93(17):e1647–59. doi: 10.1212/WNL.0000000000008081.

  17. Gordon, Brian A., Karl Friedrichsen, Matthew Brier, Tyler Blazey, Yi Su, Jon Christensen, Patricia Aldea, Jonathan McConathy, David M. Holtzman, Nigel J. Cairns, John C. Morris, Anne M. Fagan, Beau M. Ances, and Tammie L. S. Benzinger. 2016. “The Relationship between Cerebrospinal Fluid Markers of Alzheimer Pathology and Positron Emission Tomography Tau Imaging.” Brain: A Journal of Neurology 139(Pt 8):2249–60. doi: 10.1093/brain/aww139.

  18. Preische, Oliver, Stephanie A. Schultz, Anja Apel, Jens Kuhle, Stephan A. Kaeser, Christian Barro, Susanne Gräber, Elke Kuder-Buletta, Christian LaFougere, Christoph Laske, Jonathan Vöglein, Johannes Levin, Colin L. Masters, Ralph Martins, Peter R. Schofield, Martin N. Rossor, Neill R. Graff-Radford, Stephen Salloway, Bernardino Ghetti, John M. Ringman, James M. Noble, Jasmeer Chhatwal, Alison M. Goate, Tammie L. S. Benzinger, John C. Morris, Randall J. Bateman, Guoqiao Wang, Anne M. Fagan, Eric M. McDade, Brian A. Gordon, Mathias Jucker, and Dominantly Inherited Alzheimer Network. 2019. “Serum Neurofilament Dynamics Predicts Neurodegeneration and Clinical Progression in Presymptomatic Alzheimer’s Disease.” Nature Medicine 25(2):277–83. doi: 10.1038/s41591-018-0304-3.

  19. Fagan, Anne M., Mark A. Mintun, Aarti R. Shah, Patricia Aldea, Catherine M. Roe, Robert H. Mach, Daniel Marcus, John C. Morris, and David M. Holtzman. 2009. “Cerebrospinal Fluid Tau and Ptau(181) Increase with Cortical Amyloid Deposition in Cognitively Normal Individuals: Implications for Future Clinical Trials of Alzheimer’s Disease.” EMBO Molecular Medicine 1(8–9):371–80. doi: 10.1002/emmm.200900048.

  20. Bos, Isabelle, Stephanie J. B. Vos, Suzanne E. Schindler, Jason Hassenstab, Chengjie Xiong, Elizabeth Grant, Frans Verhey, John C. Morris, Pieter Jelle Visser, and Anne M. Fagan. 2019. “Vascular Risk Factors Are Associated with Longitudinal Changes in Cerebrospinal Fluid Tau Markers and Cognition in Preclinical Alzheimer’s Disease.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 15(9):1149–59. doi: 10.1016/j.jalz.2019.04.015.

  21. Fagan, Anne M., Catherine M. Roe, Chengjie Xiong, Mark A. Mintun, John C. Morris, and David M. Holtzman. 2007. “Cerebrospinal Fluid Tau/Beta-Amyloid(42) Ratio as a Prediction of Cognitive Decline in Nondemented Older Adults.” Archives of Neurology 64(3):343–49. doi: 10.1001/archneur.64.3.noc60123.

  22. Perrin, Richard J., Rebecca Craig-Schapiro, James P. Malone, Aarti R. Shah, Petra Gilmore, Alan E. Davis, Catherine M. Roe, Elaine R. Peskind, Ge Li, Douglas R. Galasko, Christopher M. Clark, Joseph F. Quinn, Jeffrey A. Kaye, John C. Morris, David M. Holtzman, R. Reid Townsend, and Anne M. Fagan. 2011. “Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer’s Disease.” PloS One 6(1):e16032. doi: 10.1371/journal.pone.0016032.

  23. Schindler, Suzanne E., Mateusz S. Jasielec, Hua Weng, Jason J. Hassenstab, Ellen Grober, Lena M. McCue, John C. Morris, David M. Holtzman, Chengjie Xiong, and Anne M. Fagan. 2017. “Neuropsychological Measures That Detect Early Impairment and Decline in Preclinical Alzheimer Disease.” Neurobiology of Aging 56:25–32. doi: 10.1016/j.neurobiolaging.2017.04.004.

  24. Fagan, Anne M., and David M. Holtzman. 2010. “Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease.” Biomarkers in Medicine 4(1):51–63. doi: 10.2217/BMM.09.83.

  25. Tarawneh, Rawan, Gina D’Angelo, Dan Crimmins, Elizabeth Herries, Terry Griest, Anne M. Fagan, Gregory J. Zipfel, Jack H. Ladenson, John C. Morris, and David M. Holtzman. 2016. “Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease.” JAMA Neurology 73(5):561–71. doi: 10.1001/jamaneurol.2016.0086.

  26. Tarawneh, Rawan, Gina D’Angelo, Elizabeth Macy, Chengjie Xiong, Deborah Carter, Nigel J. Cairns, Anne M. Fagan, Denise Head, Mark A. Mintun, Jack H. Ladenson, Jin-Moo Lee, John C. Morris, and David M. Holtzman. 2011. “Visinin-like Protein-1: Diagnostic and Prognostic Biomarker in Alzheimer Disease.” Annals of Neurology 70(2):274–85. doi: 10.1002/ana.22448.

  27. Henson, Rachel L., Eric Doran, Bradley T. Christian, Benjamin L. Handen, William E. Klunk, Florence Lai, Joseph H. Lee, H. Diana Rosas, Nicole Schupf, Shahid H. Zaman, Ira T. Lott, and Anne M. Fagan. 2020. “Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease in a Cohort of Adults with Down Syndrome.” Alzheimer’s & Dementia : Diagnosis, Assessment & Disease Monitoring 12(1). doi: 10.1002/dad2.12057.

  28. Tarawneh, Rawan, Denise Head, Samantha Allison, Virginia Buckles, Anne M. Fagan, Jack H. Ladenson, John C. Morris, and David M. Holtzman. 2015. “Cerebrospinal Fluid Markers of Neurodegeneration and Rates of Brain Atrophy in Early Alzheimer Disease.” JAMA Neurology 72(6):656–65. doi: 10.1001/jamaneurol.2015.0202.

  29. Craig-Schapiro, Rebecca, Richard J. Perrin, Catherine M. Roe, Chengjie Xiong, Deborah Carter, Nigel J. Cairns, Mark A. Mintun, Elaine R. Peskind, Ge Li, Douglas R. Galasko, Christopher M. Clark, Joseph F. Quinn, Gina D’Angelo, James P. Malone, R. Reid Townsend, John C. Morris, Anne M. Fagan, and David M. Holtzman. 2010. “YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer’s Disease.” Biological Psychiatry 68(10):903–12. doi: 10.1016/j.biopsych.2010.08.025.

  30. Piccio, Laura, Yuetiva Deming, Jorge L. Del-Águila, Laura Ghezzi, David M. Holtzman, Anne M. Fagan, Chiara Fenoglio, Daniela Galimberti, Barbara Borroni, and Carlos Cruchaga. 2016. “Cerebrospinal Fluid Soluble TREM2 Is Higher in Alzheimer Disease and Associated with Mutation Status.” Acta Neuropathologica 131(6):925–33. doi: 10.1007/s00401-016-1533-5.

  31. Craig-Schapiro, Rebecca, Max Kuhn, Chengjie Xiong, Eve H. Pickering, Jingxia Liu, Thomas P. Misko, Richard J. Perrin, Kelly R. Bales, Holly Soares, Anne M. Fagan, and David M. Holtzman. 2011. “Multiplexed Immunoassay Panel Identifies Novel CSF Biomarkers for Alzheimer’s Disease Diagnosis and Prognosis.” PloS One 6(4):e18850. doi: 10.1371/journal.pone.0018850.

  32. Kester, Maartje I., Charlotte E. Teunissen, Courtney Sutphen, Elizabeth M. Herries, Jack H. Ladenson, Chengjie Xiong, Philip Scheltens, Wiesje M. van der Flier, John C. Morris, David M. Holtzman, and Anne M. Fagan. 2015. “Cerebrospinal Fluid VILIP-1 and YKL-40, Candidate Biomarkers to Diagnose, Predict and Monitor Alzheimer’s Disease in a Memory Clinic Cohort.” Alzheimer’s Research & Therapy 7(1):59. doi: 10.1186/s13195-015-0142-1.

  33. Schindler, Suzanne E., Courtney L. Sutphen, Charlotte Teunissen, Lena M. McCue, John C. Morris, David M. Holtzman, Sandra D. Mulder, Philip Scheltens, Chengjie Xiong, and Anne M. Fagan. 2018. “Upward Drift in Cerebrospinal Fluid Amyloid β 42 Assay Values for More than 10 Years.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 14(1):62–70. doi: 10.1016/j.jalz.2017.06.2264.

  34. Mattsson, Niklas, Ulf Andreasson, Staffan Persson, Maria C. Carrillo, Steven Collins, Sonia Chalbot, Neal Cutler, Diane Dufour-Rainfray, Anne M. Fagan, Niels H. H. Heegaard, Ging-Yuek Robin Hsiung, Bradley Hyman, Khalid Iqbal, Stephan A. Kaeser, Stephan A. Käser, D. Richard Lachno, Alberto Lleó, Piotr Lewczuk, José L. Molinuevo, Piero Parchi, Axel Regeniter, Robert A. Rissman, Robert Rissman, Hanna Rosenmann, Giuseppe Sancesario, Johannes Schröder, Leslie M. Shaw, Charlotte E. Teunissen, John Q. Trojanowski, Hugo Vanderstichele, Manu Vandijck, Marcel M. Verbeek, Henrik Zetterberg, Kaj Blennow, and Alzheimer’s Association QC Program Work Group. 2013. “CSF Biomarker Variability in the Alzheimer’s Association Quality Control Program.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 9(3):251–61. doi: 10.1016/j.jalz.2013.01.010.