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Alzheimers Res Ther. 2016 Jan 29;8:4. doi: 10.1186/s13195-016-0173-2.

Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease.

Author information

1
Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Avenue, Las Vegas, NV, 89106, USA. cumminj@ccf.org.
2
Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Avenue, Las Vegas, NV, 89106, USA. zhongk@ccf.org.
3
Department of Psychology, University of Nevada, Las Vegas, NV, USA. jefferson.kinney@unlv.edu.
4
Department of Psychology, University of Nevada, Las Vegas, NV, USA. chelcie.heaney@gmail.com.
5
Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Avenue, Las Vegas, NV, 89106, USA. mollj@ccf.org.
6
Avid Pharmaceuticals, Philadelphia, PA, USA. joshi@avidrp.com.
7
Avid Pharmaceuticals, Philadelphia, PA, USA. pontecorvo@avidrp.com.
8
Avid Pharmaceuticals, Philadelphia, PA, USA. devous@avidrp.com.
9
Cleveland Clinic Quantitative Health Services, Cleveland, OH, USA. tanga@ccf.org.
10
Cleveland Clinic Quantitative Health Services, Cleveland, OH, USA. benaj@ccf.org.

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 Aβ1-40 and Aβ1-42 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 Aβ1-42 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 Aβ1-42 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.

PMID:
26822146
PMCID:
PMC4731943
DOI:
10.1186/s13195-016-0173-2
[Indexed for MEDLINE]
Free PMC Article

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