Sabbagh Laboratory
Laboratory Focus
Our laboratory focuses on applied Alzheimer’s research, including drug development and drug repurposing to achieve new treatments for Alzheimer’s disease (AD), the most common cause of dementia. We plan to accomplish this by repurposing drugs from other disciplines for AD and through translational research and clinical trials. We use both bench to bedside and bedside to bench approaches.
We also plan to test innovative biomarkers (e.g. saliva and plasma) for diagnostic and screening purposes. There is strong interest in novel diagnostic tests but most of this interest is focused on amyloid and tau in spinal fluid. We want to explore other targets and other tissues.
Another goal of our research is to re-engineer the patient experience to be more decisive and more efficient with better outcomes. This includes testing and screening even before the patient visit.
Finally, we want to make meaningful and impactful contributions to the medical and scientific literature by collaborating with and mentoring medical students and neurology residents.
Active Research Projects
Until now, the vast majority of therapeutic interventions targeting AD have focused on monotherapies to alter a single neuropathology. Unfortunately, all of these approaches have failed to meet the clinical endpoint of significantly slowing or reversing cognitive decline in AD subjects. This emphasizes the urgent need for novel therapeutic interventions to reduce several AD neuropathologies simultaneously.
Inflammation is pervasive in many neurological disorders, yet no clinical trial has demonstrated the efficacy of anti-inflammatory agents for AD. Our research group is particularly interested in drugs that lower both systemic and central inflammation, aiming prevent or slow the clinical progression of AD. Our most promising compound is the immunomodulator, anti-cancer agent lenalidomide. Lenalidomideis one of the very few pleiotropic agents that both lowers the expression of pro-inflammatory (e.g., TNFα, IL-6, IL-8), and increases the expression of anti-inflammatory cytokines (e.g., IL-10) to modulate both innate and adaptive immune responses.
In the current project, we aim to capitalize on our experience from a previous clinical trial with an analog and our preclinical data to test our central hypothesis: That lenalidomide reduces AD-associated neuroinflammation and neuropathologies, which might result in improved cognitive performances. To accomplish this, we designed a Phase IIa, proof-of-mechanism, placebo-controlled clinical study on single- and multiple-domain amnestic MCI subjects administered 10 mg/day lenalidomide for six (MCLENA2 ) or 12 months (MCLENA1).
Because lenalidomide has never been tested in the context of AD, we will monitor carefully the safety and tolerability in MCI patients. To demonstrate the engagement of lenalidomide in study subjects, we will:
- Measure inflammatory markers in the periphery every 3 months
- Measure cognitive performance via MCI-sensitive tests
- Assess target engagement (CSF markers MCLENA2 ) at the completion of dosing
- Assess impact on imaging (MCLENA 1)
This is highly significant because, if successful, lenalidomide will become one of the very few compounds capable of lowering several neuropathological features associated with AD. Furthermore, the major advantage of lenalidomide is that the drug is already FDA-approved for cancer treatment, thus it could rapidly be repurposed in a Phase III study
Assessment of Lenalidomide for Alzheimer’s Disease
This is a 30-week long, Phase Ib-IIa, double-blind, randomized, two-armed, parallel group, placebo controlled, proof-of-mechanism clinical study in early symptomatic AD subjects (i.e. amnestic mild cognitive impairment; aMCI). The primary outcome measures are the assessment of lenalidomide on inflammatory markers in CSF and blood, as well as safety and toxicity. Plasma inflammatory molecules will be investigated to assess whether one or more of these markers can serve as surrogate markers of the treatment in aMCI subjects. The secondary outcome measures are the effects of lenalidomide treatment on AD-associated (Aβ and tau) biomarkers in CSF and blood.
Active Research Project – GC-2013717 (PI: Sabbagh)
Alzheimer’s disease (AD) is a neurodegenerative disorder with several complex neuropathologies suspected to develop sequentially but that overlap over time as symptoms progress to dementia. Thus, to be effective, future intervention strategies will likely require combination therapies or pleiotropic agents to tackle several AD molecular pathogenic pathways simultaneously. For more than a decade, our group has been exploring the repurposing of immunomodulators for AD.
Recent discussions with collaborators specialized in multiple sclerosis (MS) suggest that sphingosine-1-phosphate receptor (S1PR) modulators are strong candidates for repurposing in AD. Indeed, S1PR modulators are blood brain barrier (BBB) penetrant and display pleiotropic actions, including immunomodulation and neuroprotective properties. S1P is a versatile, endogenous molecule that regulates several signaling pathways by binding to five G-protein-coupled receptors, which are expressed in high levels in cardiac, vascular, immune, and brain cells. This widespread localization of S1PR was the historical basis for pharmaceutical companies to develop oral formulations of S1PR modulators for multiple sclerosis (MS), which proved successful and resulted in two marketed compounds.
In the present project, we intend to use the most recently FDA-approved S1PR modulator, siponimod. Based on MS and animal experimentation literature, we hypothesize that siponimod could lower the rate of brain atrophy in AD subjects. In this Phase II, proof-of-concept, rigorous translational clinical study, mild AD subjects will be randomized 2:1 and receive a slow up-titration regimen of siponimod up to 1 mg/day (N=70) or placebo (N=35) for 12 months, followed by a 6-month washout period. Primary objectives are drug safety and tolerability in AD subjects, assessed via regular clinical tests throughout the dosing period. Critically, eventual treatment-emergent toxicities will drive our go/no-go decision process to pursue or stop dosing.
The secondary objective is to determine drug effect on relative annual brain atrophy rates in the two groups by comparing pre- and post-exposure volumetric MRI data. Tertiary objectives are cognition and CSF markers of AD (amyloid, tau, p-tau) and inflammation. As an exploratory objective, we will also investigate whether blood cell counts and blood biomarkers can be used as dynamic surrogate markers of drug efficacy. Because siponimod has demonstrated positive immunomodulatory and neuroprotective actions in MS, and because its toxicity profile is favorable for use in older individuals, this drug has a strong potential to alter markers of AD pathology and disease trajectory.
We are working on several additional grants, including an R61-R33 biomarker grant to explore common mechanisms between cancer and dementia. Further explorations of pomalidomide in the treatment of AD and CSF biobanking for future discoveries are also planned.
Contact Information
Marwan Sabbagh, MD, FAAN
Professor of Neurology
350 West Thomas Road
Phoenix, Arizona 85013
- Jeffrey Cummings; Gil D. Rabinovici; Alireza Atri; Paul Aisen; Liana G. Apostolova; Suzanne Hendrix; Marwan Sabbagh; Dennis Selkoe; Michael Weiner; Stephen Salloway, Aducanumab: Appropriate Use Recommendations Update, J Prev Alz Dis 2022; Published online April 5, 2022, http://dx.doi.org/10.14283/jpad.2022.34
- Marwan Sabbagh, Gary W. Small, Stuart H. Isaacson, Yasar Torres-Yaghi, Fernando Pagan & Rajesh Pahwa (2022) Unmet needs in the diagnosis and treatment of Parkinson’s disease psychosis and dementia-related psychosis, International Journal of Psychiatry in Clinical Practice, DOI: 10.1080/13651501.2022.2058406
- Rema Raman; Paul Aisen; Maria M Carrillo; Michael Detke; Joshua D Grill; Ozioma Okonkwo; Monica Rivera-Mindt; Marwan Sabbagh; Bruno Vellas; Michael Weiner; Reisa Sperling. Tackling a Major Deficiency of Diversity in Alzheimer’s Disease Therapeutic Trials: An EU/US Task Force Report. J Prev Alz Dis 2022; Published online May 13, 2022, http://dx.doi.org/10.14283/jpad.2022.50
- DeCourt B, Sabbagh MN. The importance of genomics in advancing the treatment of dementia, Lancet Neurology 2022 Published online June 10, 2022, https://doi.org/10.1016/S1474-4422(22)00234-4
- Frederick M. Lang, Jeffrey L. Cummings, Marwan Sabbagh, Paul Solomon, Merce Boada, Roy W. Jones, Giovanni Frisoni, Timo Grimmer, Bruno Dubois, Yi Mo, Mark Harnett, Sarah R. Friedhoff, Shari Coslett, Lawrence T. Friedhoff. Intepirdine as Adjunctive Therapy to Donepezil for Mild-to-Moderate Alzheimer’s Disease: A Randomised, Placebo-Controlled, Phase 3 Clinical Trial (MINDSET) Alzheimer’s & Dementia: Translational Research and Clinical Interventions 17 March 2021 https://doi.org/10.1002/trc2.12136
- Frederick M. Lang, Daniel Y. Kwon, Dag Aarsland, Brad Boeve, Babak Tousi, Mark Harnett, Yi Mo, Marwan Sabbagh. An International, Randomized, Placebo-Controlled, Phase 2b Clinical Trial of Intepirdine for Dementia with Lewy Bodies (HEADWAY-DLB) Alzheimer’s & Dementia: Translational Research and Clinical Interventions 2021; DOI: 10.1002/trc2.12171
- Steven D. Targum, Lisa Fosdick, Kristen E. Drake, Paul B. Rosenberg, Anna D. Burke, David A. Wolk, Kelly D. Foote, Wael F. Asaad, Marwan Sabbagh, Gwenn S. Smith, Andres M. Lozano, Constantine G. Lyketsos. Effect of age on clinical trial outcome in participants with probable Alzheimer’s disease, J Alzheimers Dis. 2021 Jun 16. doi: 10.3233/JAD-210530.
- Zammit, Matthew; Tudorascu, Dana; Laymon, Charles; Hartley, Sigan; Ellison , Paul ; Zaman, Shahid; Ances, Beau; Johnson, Sterling; Stone, Charles; Sabbagh , Marwan ; Mathis, Chester; Klunk, William; Cohen, Anne; Handen, Benjamin; Christian, Brad. Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in Down syndrome, Neuroimage 2021; https://doi.org/10.1016/ j.nicl.2021.102740
- Sadrolashrafi K, Craft S, DeCourt B, Adem A, Miller J., Sabbagh MN, Is Diabetes Associated with Increased Pathological Burden in Alzheimer’s? Alzheimers Dement (Amst). 2021 Nov 10;13(1):e12248. doi: 10.1002/dad2.12248. eCollection 2021
- Hartley S, Zammit M, Christian BT, Handen B, Zaman S, Sabbagh MN Gambetti B, Ances B, Tudorascu DL, Cohen A, Klunk WE, Laymon CM, Lee L. Role of Tau Deposition in Early Cognitive Decline in Down Syndrome, Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring First published: 01 April 2022 https://doi.org/10.1002/dad2.12256
- Maurizio Bergamino 1 PhD, Anna Burke 2 MD, Leslie C. Baxter 3 PhD, Richard J. Caselli 3 MD, Marwan N.Sabbagh 2 MD, Joshua Talboom 4 , PhD, Matthew Huentelman 4 , PhD, Ashley M. Stokes 1 PhDLongitudinal Assessment of Intravoxel Incoherent Motion Diffusion-Weighted MRI (IVIM-DWI) Metrics in Cognitive Decline. J Magn Reson Imaging. 2022 Mar 23. doi: 10.1002/jmri.28172. Online ahead of print.PMID: 35319142
- Michael S. Rafii, MD, PhD; Olivier Sol, MD; William C. Mobley, MD, PhD; Saskia Delpretti, PhD; Brian G. Skotko, MD, MPP; Anna D. Burke, MD; Marwan N. Sabbagh, MD; Shauna H. Yuan, MD; Robert A. Rissman, PhD; Margaret Pulsifer, PhD; Casey Evans, PhD; A. Carol Evans, BA; Gregory Beth, BS; Nicolas Fournier, PhD; Julian A. Gray, MD; Antonio Melo dos Santos, MD; Valerie Hliva, PhD; Marija Vukicevic, PhD; Marie Kosco-Vilbois, PhD; Johannes Streffer, MD; Andrea Pfeifer, PhD; Howard H. Feldman, MD. Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome A Phase 1b Randomized Clinical Trial. JAMA Neurol. doi:10.1001/jamaneurol.2022.0983