Abstract
BackgroundWe 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.MethodsTwenty 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.ResultsThere 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.ConclusionsThe 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 registrationClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0173-2) contains supplementary material, which is available to authorized users.
Highlights
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
Much current therapeutic research is focused on the amyloid hypothesis and means of redressing the imbalance between production and clearance of amyloid-β (Aβ) protein that leads to peptide aggregation, neurotoxicity, and formation of neuritic plaques [5]
We report the primary outcomes of the study
Summary
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. There is an urgent need to develop new treatments for Alzheimer’s disease (AD). AD is currently the third leading cause of death in the United States [1] and costs the economy more annually than cardiovascular disease or cancer [2]. By 2050, the annual cost of AD to the U.S economy will exceed $1 trillion [3]. All attempts to develop disease-modifying treatments for AD have failed [4]. Much current therapeutic research is focused on the amyloid hypothesis and means of redressing the imbalance between production and clearance of amyloid-β (Aβ) protein that leads to peptide aggregation, neurotoxicity, and formation of neuritic plaques [5]. Pharmaceutical approaches include reducing Aβ production, inhibiting its aggregation, and facilitating its removal [6]
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