David Holtzman, M.D.

Andrew B. and Gretchen P. Jones Professor; Professor of Developmental Biology; Associate Director of the Knight Alzheimer’s Disease Research Center; Scientific Director of the Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis

In addition to his laboratory, administrative and teaching duties, Dr. David Holtzman is involved in clinical and research activities at the Washington University Memory and Aging Project and the Alzheimer’s Disease Research Center. Dr. Holtzman has carried out ground-breaking studies of molecules involved in beta-amyloid (Aβ) metabolism (such as apoE) and the initiation of Alzheimer’s pathology and the role of vascular factors such as amyloid angiopathy in the disease. He also has contributed greatly to our understanding of how anti-amyloid antibodies affect Alzheimer’s pathology and how Aβ is cleared from the brain of Alzheimer’s disease patients.

Funded Research

These projects were made possible from Cure Alzheimer's Fund support.

Project Description Researchers Funding
APOE Consortium: Role of APOE Isoforms in Immune Responses in a Model of Tauopathy 2022


TREM2: Role in Modulating Amyloid Beta and Tau-Related Pathologies and Neurodegeneration 2017, 2019


Understanding the Effect of APOE on Tau-Mediated Neurodegeneration 2017, 2018, 2020, 2021


Characterization of Certain Human APOE Targeted Gene Replacement Mice 2016


The Biological Impact of TREM Locus Mutations in Alzheimer’s Disease 2015


Sleep and tauopathies: Effect of an anti-tau antibody 2013


Mechanisms of Retinoid X Receptor-Mediated Abeta Clearance in Alzheimers’ Disease 2011


Effect of Bexarotene on Abeta in APP Tg Mice Expressing ApoE3 and ApoE4 2011


Oligomer Collaborative Projects 2006


Core Facility for Abeta Microdialysis Drug Discovery Platform 2007, 2008, 2009


Development of Tau Microdialysis as a Method to Study Tau Metabolism, Pathophysiology and Response to Treatment 2009


Defining the Effects of Physiological Synaptic Activity on Abeta Levels: Implications for AD 2008


Anti-APOE Antibodies 2010


Selected Publications

These published papers resulted from Cure Alzheimer’s Fund support.

Cheryl E. G. Leyns, Jason D. Ulrich, Mary B. Finn, Floy R. Stewart, Lauren J. Koscal, Javier Remolina Serrano, Grace O. Robinson, Elise Anderson, Marco Colonna, David M. Holtzman TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proceedings of the National Academy of Sciences of the United States of America, 114(43), 24 Oct 2017, 11524–11529, Read More

Yang Shi, Kaoru Yamada, Shane Antony Liddelow, Scott T. Smith, Lingzhi Zhao, Wenjie Luo, Richard M. Tsai, Salvatore Spina, Lea T. Grinberg, Julio C. Rojas, Gilbert Gallardo, Kairuo Wang, Joseph Roh, Grace Robinson, Mary Beth Finn, Hong Jiang, Patrick M. Sullivan, Caroline Baufeld, Michael W. Wood, Courtney Sutphen, Lena McCue, Chengjie Xiong, Jorge L. Del-Aguila, John C. Morris, Carlos Cruchaga, Alzheimer’s Disease Neuroimaging Initiative, Anne M. Fagan, Bruce L. Miller, Adam L. Boxer, William W. Seeley, Oleg Butovsky, Ben A. Barres, Steven M. Paul, David M. Holtzman ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy, Nature, 20 Sep 2017, Read More

Susanne Krasemann, Charlotte Madore, Ron Cialic, Caroline Baufeld, Narghes Calcagno, Rachid El Fatimy, Lien Beckers, Elaine O’Loughlin, Yang Xu, Zain Fanek, David J. Greco, Scott T. Smith, George Tweet, Zachary Humulock, Tobias Zrzavy, Patricia Conde-Sanroman, Mar Gacias, Zhiping Weng, Hao Chen, Emily Tjon, Fargol Mazaheri, Kristin Hartmann, Asaf Madi, Jason D. Ulrich, Markus Glatzel, Anna Worthmann, Joerg Heeren, Bogdan Budnik, Cynthia Lemere, Tsuneya Ikezu, Frank L. Heppner, Vladimir Litvak, David M. Holtzman, Hans Lassmann, Howard L. Weiner, Jordi Ochando, Christian Haass, Oleg Butovsky The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases, Immunity, 47(3), 19 Sep 2017, 566-581, Read More

Tyler K. Ulland, Wilbur M. Song, 7, Stanley Ching-Cheng Huang, Jason D. Ulrich, Alexey Sergushichev, Wandy L. Beatty, Alexander A. Loboda, Yingyue Zhou, Nigel J. Cairns, Amal Kambal, Ekaterina Loginicheva, Susan Gilfillan, Marina Cella, Herbert W. Virgin, Emil R. Unanue, Yaming Wang, Maxim N. Artyomov, David M. Holtzman, Marco Colonna TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease, Cell, 170(4), 10 Aug 2017, 649–663, Read More

Jason D. Ulrich, Tyler K. Ulland, Marco Colonna, and David M. Holtzman Elucidating the Role of TREM2 in Alzheimer’s Disease, Neuron, 94, 19 Apr 2017, 237-248, Read More, Download Paper

Jerrah K. Holth, Thomas E. Mahan, Grace O. Robinson, Andreia Rocha, David M. Holtzman Altered sleep and EEG power in the P301S Tau transgenic mouse model, Ann Clin Transl Neurol, 4(3), 15 Feb 2017, 180-190, Read More

C. Ising, M. Stanley and D.M. Holtzman Current thinking on the mechanistic basis of Alzheimer’s and implications for drug development, Clinical Pharmacology & Therapeutics, 98(5), November 2015, 469–471, Read More

Jee Hoon Roh and David M. Holtzman Is there a link between the sleep–wake cycle and Alzheimer’s pathology?, Future Neurology, 10(3), 05/08/2015, 183-186, Read More

Yuk Yee Leung, Jon B. Toledo, Alexey Nefedov, Robi Polikar, Nandini Raghavan, Sharon X. Xie, Michael Farnum, Tim Schultz, Young Baek, Vivianna M. Van Deerlin, William T. Hu, David M. Holtzman, Anne M. Fagan, Richard J. Perrin, Murray Grossman, Holly D. Soares, Mitchel A. Kling, Matthew Mailman, Steven E. Arnold, Vaibhav A. Narayan, Virginia M-Y. Lee, Leslie M. Shaw, David Baker, Gayle M. Wittenberg, John Q. Trojanowski, and Li-San Wang Identifying amyloid pathology–related cerebrospinal fluid biomarkers for Alzheimer’s disease in a multicohort study, Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 1(3), September 2015, 339-348, Read More

Brendan P Lucey, David M Holtzman How amyloid, sleep and memory connect, Nature Neuroscience, 18, June 25, 2015, 933–934, Read More

Erik S Musiek & David M Holtzman Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’, Nature Neuroscience, May 2015, 800-806, Read More

Kiran Yanamandra, Hong Jiang, Thomas E. Mahan, Susan E. Maloney, David F. Wozniak, Marc I. Diamond and David M. Holtzman Anti-tau antibody reduces insoluble tau and decreases brain atrophy, Annals of Clinical and Translational Neurology, 2(3), March 2015, 278–288, Read More

Miranda M Lim, Jason R Gerstner. David M Holtzman The sleep–wake cycle and Alzheimer’s disease: what do we know?, Neurodegenerative Disease Management, Vol. 4, No. 5, 351-362, Read More

Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, Cairns NJ, Morris JC, Holtzman DM, Fagan AM Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study, The Lancet Neurology, 12(10), September 4, 2013, 957-965, Read More

Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls, Ann. Neurol, 73(1), January 1, 2013, 104-119, Read More

Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Kim J, Stewart FR, Basak JM, Holtzman DM Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis, J Exp Med., 209(12), Nov 19, 2012, 2149-56, Read More

Jee Hoon Roh,1,2,3 Yafei Huang,1 Adam W. Bero,1,2,3 Tom Kasten,1 Floy R. Stewart,1,2,3 Randall J. Bateman,1,2,3 David M. Holtzman1,2,3,4* Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of Amyloid-b in Mice with Alzheimer’s Disease Pathology, Science Translational Medicine Home, Vol. 4, Issue 150, September 5, 2012, Read More

Bero AW, Bauer AQ, Stewart FR, White BR, Cirrito JR, Raichle ME, Culver JP, Holtzman DM Bidirectional relationship between functional connectivity and amyloid-β deposition in mouse brain, J Neurosci., 32(13), Mar 28, 2012, 4334-40, Read More

Schwetye KE, Cirrito JR, Esparza TJ, Mac Donald CL, Holtzman DM, Brody DL Traumatic brain injury reduces soluble extracellular amyloid-β in mice: A methodologically novel combined microdialysis-controlled cortical impact study, Neurobiology of Disease, Volume 40, Issue 3, Dec 2010, 555-564, Read More

Zeng C, Pan F, Jones LA, Lim MM, Griffin EA, Sheline YI, Mintun MA, Holtzman DM, Mach RH Evaluation of 5-ethynyl-2′-deoxyuridine staining as a sensitive and reliable method for studying cell proliferation in the adult nervous system, Brain Research, Volume 1319, Mar 10 2010, 21-32, Read More

Clifford DB, Fagan AM, Holtzman DM, Morris JC, Teshome M, Shah AR, Kauwe JSK CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease, Neurology, 73(23), December 8, 2009, 1982-7, Read More

Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle, Science, 326(5955), Nov 13, 2009, 1005-7, Read More

Yan P, Bero AW, Cirrito JR, Xiao Q, Hu X, Wang Y, Gonzales E, Holtzman DM, Lee J-M Characterizing the Appearance and Growth of Amyloid Plaques in APP/PS1 Mice, The Journal of Neuroscience, 29(34), Aug 26 2009, 10706-10714, Read More

Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses, Chemical Biology, 4:8, July 22, 2009, 673-684, Read More

Cao C, Cirrito JR, Lin X, Wang L, Verges DK, Dickson A, Mamcarz M, Zhang C, Mori T, Arendash GW, Holtzman DM, Potter H Caffeine suppresses beta-amyloid levels in plasma and brain of Alzheimer’s transgenic mice., Journal of Alzheimer's disease, July 2009, Read More

Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM Amyloid-beta dynamics correlate with neurological status in the injured human brain, Science, 321(5893), Aug 29, 2008, 1221-4, Read More

Brody DL, Holtzman DM Active and Passive Immunotherapy for Neurodegenerative Disorders, Annu Rev Neurosci., 31, July 2008, 175–193, Read More

Cirrito JR, Kang J, Lee J, Stewart FR, Verges D, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo., Neuron, 58(1), April 10, 2008, 42-51, Read More

Kang JE, Cirrito JR, Dong H, Csernansky JG, Holtzman DM Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity, Neurology, Vol. 75/no. 7, June 2007, 595-602, Read More