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

Jeffrey L. Cummings, Kate Zhong, Jefferson W. Kinney, Chelcie Heaney, Joanne Moll-Tudla, Abhinay Joshi, Michael Pontecorvo, Michael Devous, Anne Tang, James Bena

Research output: Contribution to journalArticlepeer-review

132 Scopus citations


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: identifier NCT01782742. Registered 29 January 2013.

Original languageEnglish (US)
Article number4
JournalAlzheimer's Research and Therapy
Issue number1
StatePublished - Jan 29 2016


  • Alzheimer's disease
  • Amyloid
  • ApoE genotype
  • Bexarotene
  • Clinical trial
  • MRI
  • PET

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience


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