David M. Holtzman

David M. Holtzman (born July 31, 1961) is an American neurologist and neuroscientist known for his work exploring the biological mechanisms underlying neurodegeneration, with a focus on Alzheimer's disease (AD). He is the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology, Scientific Director of the Hope Center for Neurological Disorders, and Director of the Knight Alzheimer's Disease Research Center at Washington University School of Medicine in St. Louis, Missouri. Holtzman served as Chair of the Department of Neurology at Washington University from 2003 to 2021. His laboratory is known for examining how apoE4 contributes to Alzheimer's disease, how sleep modulates amyloid beta in the brain, and the contributions of microglia to AD pathology.

Early life and education Holtzman was born in St. Louis, Missouri. He pursued a six-year combined Bachelor's and Medical Degree at Northwestern University in Evanston, Illinois, obtaining his Bachelor of Science in Medical Education in 1983 and his Medical Degree in 1985. His postdoctoral research, conducted under the mentorship of William C. Mobley, focused on developing mouse models of neonatal stroke and neurodegeneration and on the role of neurotrophins in the brain.

Career In 1994, Holtzman joined Washington University in St. Louis as an assistant professor in the Departments of Neurology and Developmental Biology. He was promoted to associate professor in 2000 and to full professor in 2002. In 2003, he was appointed Chairman of the Department of Neurology, a position he held until 2021, and in 2015 he became Scientific Director of the Hope Center for Neurological Disorders. The company has commercialized cerebrospinal fluid and plasma biomarker tests for Alzheimer's disease based on antibodies developed in the Holtzman laboratory. He served as President of the American Neurological Association from 2017 to 2019.

Research ApoE and Alzheimer's disease The apolipoprotein E gene (APOE) is the strongest known genetic risk factor for late-onset Alzheimer's disease. Carrying one copy of the ε4 isoform increases AD risk approximately 3.7-fold, while two copies increase risk approximately 12-fold relative to the ε3 allele; the ε2 allele is associated with reduced risk. Holtzman's laboratory has shown that apoE influences AD pathogenesis primarily through its effects on soluble Aβ clearance and aggregation, with different isoforms of apoE having differential effects on soluble Aβ clearance. More recently, the laboratory showed that apoE4, particularly as produced by astrocytes and reactive microglia, strongly exacerbates tau-mediated neurodegeneration via the brain's innate and adaptive immune system, a mechanism relevant to disease progression and to primary tauopathies.

Immunotherapy approaches The Holtzman laboratory has investigated both anti-Aβ and anti-tau immunotherapeutic strategies. In 2001, the laboratory demonstrated that peripheral administration of an anti-Aβ antibody (m266) altered the equilibrium of Aβ across the central nervous system and blood plasma, leading to increased Aβ sequestration in plasma and reduced amyloid burden in the brain. This antibody was subsequently licensed to Eli Lilly and humanized as solanezumab, which advanced to clinical trials in mild Alzheimer's disease. The laboratory also developed anti-tau antibodies shown to block tau aggregate seeding in vitro and reduced pathology and improved cognition in animal models; one such antibody was licensed to AbbVie and progressed to phase 2 clinical trials.

More recently, the laboratory identified that a non-lipidated form of apoE is selectively present in amyloid plaques and cerebral amyloid angiopathy (CAA). An antibody targeting this form of apoE (HAE-4) was found to clear amyloid plaques and CAA and to improve CAA-associated vascular dysfunction in preclinical models.

Synaptic activity and amyloid-beta The laboratory was among the first to demonstrate that synaptic activity directly regulates levels of soluble, monomeric Aβ in the brain interstitial fluid in vivo, specifically through synaptic vesicle release and recycling. Subsequent work showed that the regional pattern of Aβ deposition in the human brain, beginning in areas associated with the default mode network, correlates with greater metabolic and synaptic activity in those regions over a lifetime.

Sleep and neurodegeneration The Holtzman laboratory has made advances in understanding how the sleep–wake cycle influences the metabolism of Aβ and tau in the brain. The laboratory demonstrated that levels of Aβ and tau in brain interstitial fluid and cerebrospinal fluid are higher during wakefulness and lower during sleep, and that these fluctuations are driven by differences in synaptic activity and orexin signaling. Sleep deprivation and orexin administration were found to acutely and chronically increase Aβ deposition, while pharmacological promotion of sleep and orexin receptor antagonists reduced Aβ.

TREM2, microglia, and tau pathology Over more than a decade, the laboratory has investigated the role of microglia and specific microglial genes, particularly TREM2 and APOE, in modulating neurodegeneration in the context of both Aβ and tau pathology. The laboratory demonstrated that microglia are key effectors of Aβ-induced tau seeding and spreading in the brain, and that TREM2, apoE, and the gut microbiome influence these processes. Work from the laboratory also showed that T cell infiltration, driven by microglial signaling, contributes to neurodegeneration in tauopathy.

Biomarker development The Holtzman laboratory developed two technical approaches that have enabled detailed study of protein metabolism in the central nervous system: a protein microdialysis method allowing measurement of proteins as frequently as every 30 minutes in the brain interstitial fluid of awake rodents and humans, and a metabolic labeling technique using stable isotope-labeled amino acids to measure rates of protein synthesis and clearance in cerebrospinal fluid and brain tissue. 2003 Potamkin Award for Alzheimer's Disease Research, American Academy of Neurology 2004 Elected member, American Society for Clinical Investigation 2008 Elected member, National Academy of Medicine (then Institute of Medicine) 2013 Chancellor's Award for Innovation and Entrepreneurship, Washington University 2015 Carl and Gerty Cori Faculty Achievement Award, Washington University 2021 Rainwater Annual Prize for Outstanding Innovation in Neurodegenerative Research, Rainwater Charitable Foundation 2026 American Innovator Award, Bayh-Dole Coalition

Selected publications