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Cited by 190Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Double-blind, placebo-controlled, proof-of-concept trial of bexarotene in moderate Alzheimer’s disease

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Cummings, Jeffrey L., Zhong, Kate, Kinney, Jefferson W., Heaney, Chelcie, Moll-Tudla, Joanne, Joshi, Abhinay, Pontecorvo, Michael, Devous, Michael +2 more·2016·Alzheimer's Research & Therapy
DOI 10.1186/s13195-016-0173-2PMC PMC4731943
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Abstract

Background: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer’s disease (AD) in a proof-of-concept trial. Methods: Twenty patients with AD [Mini Mental State Examination (MMSE) score 10–20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer’s Disease Assessment Scale–Cognitive subscale, Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ 1–40 and Aβ 1–42 measurements were collected as biomarker outcomes. Results: There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ 1–42 and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure. Conclusions: The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ 1–42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies. Trial registration: ClinicalTrials.gov identifier NCT01782742 . Registered 29 January 2013.

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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 [211]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Clinical trials have shown reduction in cortical amyloid levels with bexarotene.

    “clinical trials have shown reduction in cortical amyloid levels”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [71]

    The Discussion reports reduced cortical amyloid after bexarotene treatment in ApoE4 noncarriers. But it also states that the trial’s primary outcome was negative, with no difference from placebo when all patients were analyzed. The claim omits that important subgroup limitation. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Bexarotene has been shown to be less effective against ApoE4 carriers than noncarriers.

    “bexarotene has been shown to be less effective against ApoE4 carriers than noncarriers (71)”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [71]

    The Results (Outcomes) report reduced brain amyloid in ApoE4 noncarriers after four weeks of bexarotene, but no significant reduction in carriers. The claim overstates this biomarker finding as general effectiveness: the Discussion says the trial’s primary outcome was negative, there were no significant cognitive changes, and the genotype subgroups were small. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Side effects, particularly triglyceride accumulation, have been observed with bexarotene.

    “side effects, particularly triglyceride accumulation, have been observed (71)”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [71]

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Authors
Cummings, J. L., Zhong, K., Kinney, J. W., Heaney, C., Moll-Tudla, J., Joshi, A., Pontecorvo, M., Devous, M., Tang, A., & Bena, J.
Affiliations
  • Cleveland Clinic (US)
  • University of Nevada, Las Vegas (US)
  • Philadelphia Foundation (US)
Corresponding author
Cummings, Jeffrey L.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2016-01-29
Volume
8
Issue
1
Pages
4-4
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-016-0173-2
PMC
PMC4731943
OpenAlex
W2272900632
Cited by
190
References
13
Citations by year
2026: 10 · 2025: 19 · 2024: 21 · 2023: 19 · 2022: 16 · 2021: 21 · 2020: 24 · 2019: 25 · 2018: 13 · 2017: 8 · 2016: 13 · 2013: 1
FWCI
15.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (P20GM109025)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
bexarotene, retinoid X receptor agonist, Alzheimer's disease, brain amyloid, amyloid imaging, florbetapir, APOE ε4, triglycerides, cognitive function, activities of daily living, neuropsychiatric symptoms
MeSH terms
Bexarotene, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Double-Blind Method, Female, Humans, Male, Middle Aged, Peptide Fragments, Tetrahydronaphthalenes, Amyloid beta-Peptides, Treatment Outcome, Retinoid X Receptors, Positron-Emission Tomography

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