A randomized controlled study to evaluate the effect of bexarotene on amyloid‐β and apolipoprotein E metabolism in healthy subjects
Open accessAbstract
Introduction: We conducted a phase Ib proof of mechanism trial to determine whether bexarotene (Targretin) increases central nervous system (CNS) apolipoprotein E (apoE) levels and alters Aβ metabolism in normal healthy individuals with the APOE ε3/ε3 genotype. Methods: We used stable isotope labeling kinetics (SILK‐ApoE and SILK‐Aβ) to measure the effect of bexarotene on the turnover rate of apoE and Aβ peptides and stable isotope spike absolute quantitation (SISAQ) to quantitate their concentrations in the cerebrospinal fluid (CSF). Normal subjects were treated for 3 days with bexarotene (n = 3 women, 3 men, average 32 years old) or placebo (n = 6 women, average 30.2 years old) before administration of C 13 ‐leucine and collection of plasma and CSF over the next 48 hours. Bexarotene concentrations in plasma and CSF were also measured. Results: Oral administration of bexarotene resulted in plasma levels of 1 to 2 μM; however, only low nM levels were found in CSF. Bexarotene increased CSF apoE by 25% but had no effect on metabolism of Aβ peptides. Discussion: Bexarotene has poor CNS penetration in normal human subjects. Drug treatment resulted in a modest increase in CSF apoE levels. The absence of an effect on Aβ metabolism is likely reflective of the low CNS levels of bexarotene achieved. This study documents the utility of SILK‐ApoE technology in measuring apoE kinetics in humans. Trial Registration: This trial is registered at clinicaltrials.gov ( NCT02061878 ).
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In phase Ib and II trials, bexarotene increased cerebrospinal fluid APOE by only 25% and failed to reduce PET Aβ burden or alter brain Aβ metabolism, probably owing to poor BBB penetration, although it caused hyperlipidaemia in most participants.
“in phase Ib and II trials, bexarotene increased cerebrospinal fluid APOE by only 25% and failed to reduce PET Aβ burden or alter brain Aβ metabolism, probably owing to poor BBB penetration, although it caused hyperlipidaemia in most participants210,211.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [210]
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- Authors
- Ghosal, K., Haag, M., Verghese, P. B., West, T., Veenstra, T., Braunstein, J. B., Bateman, R. J., Holtzman, D. M., & Landreth, G. E.
- Affiliations
- ReXceptor LLC Cleveland OH USA
- C2N Diagnostics (United States) (US)
- Washington University in St. Louis (US)
- Case Western Reserve University (US)
- Corresponding author
- Landreth, Gary E.
- ORCID
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2016-06
- Volume
- 2
- Issue
- 2
- Pages
- 110-120
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC5644280
- OpenAlex
- W2470345034
- Cited by
- 73
- References
- 16
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 10 · 2019: 11 · 2018: 6 · 2017: 4 · 2013: 1
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- DigitalCommons-Cedarville (Cedarville University) (submittedVersion)
- Funders
- BrightFocus Foundation
- Case Western Reserve University
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- bexarotene, apolipoprotein E, amyloid-beta metabolism, cerebrospinal fluid, CNS penetration, pharmacokinetics, Alzheimer's disease
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