Evidence map›Paper›PMID 36581878›Full record

Trial reportAlzheimer's research & therapy2022

CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer's disease.

Alan J Lerner, Steven E Arnold, Erin Maxfield, Aaron Koenig, Maria E Toth, Brooke Fortin, Natalia Mast, Bianca A Trombetta, John Denker, Andrew A Pieper and 3 more

2 registry-linked trialsOpen access · goldAbstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Alzheimer's research & therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
6.8field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03706885 phase1completednot on this map

A Proof-of-Concept Clinical Research Study of Efavirenz in Patients With Alzheimer's Disease

TypeinterventionalSponsorCase Western Reserve UniversityRan2018 to 2022Enrolled5ConditionsAlzheimer Disease, Early OnsetArmsSustiva Pill
NCT07482085 phase3not yet recruitingnot on this mapstarted 2026, after this paper: background citation

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Study to Evaluate the Efficacy and Safety of Efavirenz in Patients With Creutzfeldt-Jakob Disease

TypeinterventionalSponsorXuanwu Hospital, BeijingRan2026 to 2028Enrolled246ConditionsCreutzfeldt-Jakob DiseaseArmsEfavirenz, Placebo
3 · Its place in the literature

Who cites it

28 citing papers in PubMed, 33 citations in OpenAlex.

  1. Efficacy and safety of efavirenz in Niemann-Pick disease type C.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025
    Trial
  2. Article
  3. Review
  4. Article
  5. Review
  6. Review
  7. Review
  8. Review
  9. Review
  10. Review
  11. Review
  12. Article
  13. Review
  14. Article
  15. Review
  16. Review
  17. Review
  18. Review
  19. Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 1 country.

Alan J LernerBrain Health and Memory Center, Neurological Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44122, USA.
Steven E ArnoldAlzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
Erin MaxfieldDepartment of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
Aaron KoenigAlzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
Maria E TothBrain Health and Memory Center, Neurological Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44122, USA.
Brooke FortinAlzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
Natalia MastDepartment of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
Bianca A TrombettaAlzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
John DenkerDepartment of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
Andrew A PieperHarrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
Curtis TatsuokaDepartment of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
Sangeetha RaghupathyDepartment of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
Irina A PikulevaDepartment of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA. iap8@case.edu.
Case Western Reserve University · USMassachusetts General Hospital · USGeriatric Research Education and Clinical Center · US

Funding

Translational and Therapeutics CoreP30AG072959 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI Mark Lloyd Cohen · 2021 to 2026
$23.9M
TISSUE CULTURE AND HYBRIDOMA MODULEP30EY011373 · NEI · CASE WESTERN RESERVE UNIVERSITY · PI Irina A Pikuleva · 1997 to 2026
$17.7M
Translational Therapeutics CoreP30AG062428 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI BEKRIS, LYNN · 2019 to 2020
$5.0M
NEI NIH HHS P30 EY011373NIA NIH HHS P30 AG062428NIA NIH HHS P30 AG072959
6 · The paper itself

Abstract

backgroundEfavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer's disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. 

methodsThis pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain.

resultsIn subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects.

conclusionsOur findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug's effects on AD biomarkers and clinical symptomatology.

trial registrationClinicalTrials.gov, NCT03706885.

Indexed as

Alzheimer DiseaseAlkynesBenzoxazinesBrainCholesterolCholesterol 24-HydroxylaseCyclopropanesHumansPilot ProjectsAlkynesBenzoxazinesCholesterolCholesterol 24-HydroxylaseCyclopropanesefavirenz24-HydroxycholesterolAlzheimer’s diseaseCYP46A1EfavirenzStable isotope labeling kinetics

Identifiers

PMID36581878
PMCPMC9797897
OpenAlexW4313441615

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.