In 1994, Holtzman became an assistant professor at Washington University in St. Louis. By 2002, Holtzman was promoted to Associate Professor of Neurology, and by 2003, he was promoted to Full Professor in the Departments of Neurology and Developmental Biology at Washington University. In 2003, he also became the Chairman of the Department of Neurology, and in 2015 he became the Scientific Director of the Hope Center for Neurological Disorders. The Holtzman Lab is dedicated to exploring the biological mechanisms underlying neurodegeneration. Holtzman's work has studied mechanisms by which apoE, amyloid beta, and tau metabolism are implicated in neurodegeneration in the context of Alzheimer's disease.
Apolipoprotein E and Alzheimer's disease Holtzman and his lab have examined the role of apoE in AD pathogenesis. Both the ε4 and ε2 APOE alleles increase the risk of developing AD, with an approximately 12-fold AD risk for those with two copies of ε4
allele.
Immunotherapeutic approaches for Alzheimer's disease In 2001, Holtzman and his team published a paper showing that administration of the anti-Aβ antibody (m266) in mice changes the equilibrium of Aβ across the CNS and
blood plasma leading to increased Aβ sequestration in plasma which reduces the burden of Aβ in the brain. This antibody, m266, was licensed to Eli Lilly and humanized. Using the humanized anti-Aβ antibody,
Solanezumab, Eli Lilly began a series of clinical trials to discern the therapeutic potential of anti-Aβ immunotherapy in humans with AD. Results of these trials were disappointing. Solanezunmab treatment did not meet the primary endpoint of the clinical trials in mild AD, however, a
clinical trial known as A4 in “presymptomatic” AD is still ongoing. Holtzman's lab has also focused on anti-tau immunotherapeutic approaches to treating AD, and this approach is now in phase II clinical trials following licensing of an anti-tau antibody his lab developed with
AbbVie.
Amyloid and Synaptic Activity Along with other groups, Holtzman and his team were able to discern that synaptic activity influences Aβ levels in the brain. They also found that Aβ deposition is brain region dependent, specifically correlating with regions involved in the
default mode network. These findings suggest that increased metabolic demands and activity levels lead to higher soluble Aβ loads in these brain regions involved in the default mode network.
Sleep and Alzheimer’s Disease The Holtzman lab has made important advances in our understanding of how sleep cycles influence Aβ concentrations in the brain interstitial fluid and
Cerebrospinal Fluid. They found that Aβ and tau are higher during wakefulness and lower during sleep, and that these differences in Aβ and tau dynamics are driven by synaptic activity differences and orexin signaling. Following this work, Holtzman and his team found that once Aβ has been deposited, it results in sleep disruptions and further Aβ aggregation in a positive feedback loop promoting increased pathology. == Awards and honors ==