David Michael Holtzman, M.D.

The Andrew B. and Gretchen P. Jones Professor of Neurology; Head, Department of Neurology, Washington University, St. Louis
Charlotte and Paul Hagemann Professor of Neurology and Molecular Biology and Pharmacology
Associate Director, Alzheimer's Disease Research Center
Scientific Director, Hope Center for Neurological Disorders

In addition to his laboratory, administrative and teaching duties, Dr. 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

Project Description Researchers Funding
Understanding the Effect of APOE on Tau-Mediated Neurodegeneration

APOE is the strongest genetic risk factor for Alzheimer’s disease, with the APOE4 isoform greatly increasing risk. We still do not completely understand how APOE increases AD risk. We have recently found that APOE4 greatly increases brain degeneration and neuronal loss that is mediated by a key protein in AD, tau, in a mouse model. We will try to better understand how APOE4 is resulting in greater brain damage. In addition, we will determine whether we can decrease APOE levels in the brain and, by doing so, block nerve cell loss and neurodegeneration.

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

Whole Genome Sequencing has identified certain polymorphisms affecting genes encoding triggering receptors expressed on myeloid cells (TREMs) with increased risk of non-familial (sporadic) Alzheimer's disease. TREM signaling is known to be important in the innate immune response, particularly in the inflammatory response. However, the relationship between the function of TREM receptors and Alzheimer's disease pathology is largely unresolved.

2015 to 2016

Characterization of Certain Human APOE Targeted Gene Replacement Mice

APOE4 is the strongest identified genetic risk factor for late-onset Alzheimer’s disease. Strong evidence from Abeta-deposition mouse models and humans indicate that APOE4 influences the metabolism of Abeta within the brain, which promotes Abeta plaque pathology. The precise mechanism(s) by which APOE isoforms influence Abeta are not completely clear, although numerous in vivo and in vitro studies suggest that APOE4 slows the clearance of Abeta from the brain and facilitates the aggregation of monomeric Abeta.

Sleep and tauopathies: Effect of an anti-tau antibody

In neurodegenerative diseases known as the tauopathies (e.g. progressive supranuclear palsy, Alzheimer disease), there is progressive degeneration of specific brain regions that account for the symptoms and signs of each disease.  Accumulation of aggregated forms of the protein tau in structures known as neurofibrillary tangles and dystrophic neurites in these brain regions correlates well with functional decline in cognition, motor, and other functions.

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

The goal of this project is to determine the effects of bexarotene on both Abeta and ApoE metabolism in the presence of human Abeta and human ApoE isoforms (any of two or more functionally similar proteins that have a similar but different amino acid sequence) because it is relevant to potential effects of similar drugs in humans.

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

The goal of this project is to investigate the mechanisms through which RXRs (retinoid x nuclear receptor) promote amyloid clearance from the brain.

Anti-APOE Antibodies

In this project, the researchers hypothesize that targeting apoE, a component of amyloid plaques, can result in less Aβ aggregation in the brain and decreased Aβ-related pathology and that this treatment will have fewer side effects than the use of anti-Aβ antibodies. The project will test this hypothesis in this proposal in the context of human apoE isoforms.

Core Facility for Abeta Microdialysis Drug Discovery Platform

In collaboration with an anonymous funder, Cure Alzheimer’s Fund is supporting development of a facility to measure the concentration of Amyloid-beta in real time in the brain of living, behaving mouse models that develop features of AD. The model enables screening for drugs that lower Amyloid-beta directly in the brain in relatively high throughput.

2007 to 2009

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

The hypothesis of this proposal is that a method can be developed to measure tau levels in the extracellular space of the brain (interstitial fluid–ISF) and that assessment of ISF tau in both normal mice as well as a variety of animal models that develop AD pathology will provide new insights into tau metabolism and the relationship between Aβ and tau in AD. If this method development is successful, it has a chance to tell us more about the pathophysiology of AD as well as a provide a novel way to screen for new AD treatments.

Oligomer Collaborative Projects

A collaboration of members of the Research Consortium, a member of the Cure Alzheimer’s Fund Science Advisory Board and non-Cure Alzheimer’s Fund-affiliated researchers hypothesizes that an abnormal increase in levels of synaptic Abeta and, particularly, Abeta oligomers may lead to synaptic dysfunction, cognitive decline and eventually dementia. This highly innovative collaborative project will address how Abeta oligomers are formed and which types detrimentally impact synaptic dysfunction and neuronal survival in the brain.

2006 to 2008

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

The objective of this proposal is to determine the effect of physiological alterations in neuronal activity on ISF Aβ levels in vivo. Such information may provide important information as to how to potentially regulate the probability of whether or not Aβ will or will not ultimately aggregate in the brain and initiate the process we know of as AD. We will utilize in vivo microdialysis with concurrent electrophysiological recordings to determine how physiological changes in neuronal activity dynamically affects ISF Aβ.


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
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
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
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
Vitaliy Ovod, Kara N. Ramsey, Kwasi G. Mawuenyega, Jim G. Bollinger, Terry Hicks, Theresa Schneider, Melissa Sullivan, Katrina Paumier, David M. Holtzman, John C. Morris, Tammie Benzinger, Anne M. Fagan, Bruce W. Patterson, Randall J. Bateman, Amyloid beta concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis, Alzheimers & Dementia, 13(8), Aug 2017, 841-849
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
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
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
Jee Hoon Roh and David M. Holtzman, Is there a link between the sleep–wake cycle and Alzheimer's pathology?, Future Neurology, 10(3), 2015, 183-186
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
Brendan P Lucey, David M Holtzman, How amyloid, sleep and memory connect, Nature Neuroscience , 18, June 25, 2015, 933–934
Erik S Musiek & David M Holtzman, Three dimensions of the amyloid hypothesis: time, space and 'wingmen', Nature Neuroscience, May 2015, 800-806
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Brody DL, Holtzman DM, Active and Passive Immunotherapy for Neurodegenerative Disorders, Annu Rev Neurosci., 31, July 2008, 175–193
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
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