title: Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier NCT01782742 . Registered 29 January 2013.
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Avenue, Las Vegas, NV, 89106, USA. cumminj@ccf.org.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Cummings
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Avenue, Las Vegas, NV, 89106, USA. zhongk@ccf.org.
authors.forename: Kate
authors.initials: K
authors.lastname: Zhong
authors.affiliation: Department of Psychology, University of Nevada, Las Vegas, NV, USA. jefferson.kinney@unlv.edu.
authors.forename: Jefferson W
authors.initials: JW
authors.lastname: Kinney
authors.affiliation: Department of Psychology, University of Nevada, Las Vegas, NV, USA. chelcie.heaney@gmail.com.
authors.forename: Chelcie
authors.initials: C
authors.lastname: Heaney
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Avenue, Las Vegas, NV, 89106, USA. mollj@ccf.org.
authors.forename: Joanne
authors.initials: J
authors.lastname: Moll-Tudla
authors.affiliation: Avid Pharmaceuticals, Philadelphia, PA, USA. joshi@avidrp.com.
authors.forename: Abhinay
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Avid Pharmaceuticals, Philadelphia, PA, USA. pontecorvo@avidrp.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Pontecorvo
authors.affiliation: Avid Pharmaceuticals, Philadelphia, PA, USA. devous@avidrp.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Devous
authors.affiliation: Cleveland Clinic Quantitative Health Services, Cleveland, OH, USA. tanga@ccf.org.
authors.forename: Anne
authors.initials: A
authors.lastname: Tang
authors.affiliation: Cleveland Clinic Quantitative Health Services, Cleveland, OH, USA. benaj@ccf.org.
authors.forename: James
authors.initials: J
authors.lastname: Bena
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood; D001057:Apolipoproteins E / Q000235:genetics; D000077610:Bexarotene; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood; D049268:Positron-Emission Tomography; D047488:Retinoid X Receptors / Q000009:adverse effects / Q000819:agonists*; D013764:Tetrahydronaphthalenes / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000077610:Bexarotene
references.citation: Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-9
references.pmid: 9236950
references.citation: Annu Rev Pharmacol Toxicol. 2014;54:381-405
references.pmid: 24392696
references.citation: Alzheimers Dement. 2015 Mar;11(3):332-84
references.pmid: 25984581
references.citation: Neurology. 1994 Dec;44(12):2308-14
references.pmid: 7991117
references.citation: Science. 2013 May 24;340(6135):924-f
references.pmid: 23704555
references.citation: Science. 2013 May 24;340(6135):924-e
references.pmid: 23704554
references.citation: Mol Cell Neurosci. 2015 May;66(Pt A):3-11
references.pmid: 25748120
references.citation: Alzheimers Dement. 2011 May;7(3):e13-44
references.pmid: 21550318
references.citation: J Alzheimers Dis. 2015;46(2):471-82
references.pmid: 25777514
references.citation: Science. 2013 May 24;340(6135):924-d
references.pmid: 23704553
references.citation: Science. 2013 May 24;340(6135):924-c
references.pmid: 23704552
references.citation: Lancet Neurol. 2014 Jun;13(6):614-29
references.pmid: 24849862
references.citation: N Engl J Med. 2013 Apr 4;368(14):1326-34
references.pmid: 23550670
references.citation: Science. 2012 Mar 23;335(6075):1503-6
references.pmid: 22323736
references.citation: Neurology. 1993 Nov;43(11):2412-4
references.pmid: 8232972
references.citation: N Engl J Med. 2012 Aug 9;367(6):488-90
references.pmid: 22873528
references.citation: N Engl J Med. 2012 Aug 9;367(6):570-2
references.pmid: 22873540
references.citation: Nat Rev Drug Discov. 2014 Jun;13(6):419-31
references.pmid: 24833294
references.citation: Expert Rev Anticancer Ther. 2004 Apr;4(2):180-8
references.pmid: 15056048
references.citation: Neurobiol Dis. 2014 Dec;72 Pt A:13-21
references.pmid: 24844148
references.citation: Dement Geriatr Cogn Disord. 2013;35(1-2):1-22
references.pmid: 23307039
references.citation: J Alzheimers Dis. 2011;26(2):377-85
references.pmid: 21654062
references.citation: J Psychiatr Res. 1975 Nov;12(3):189-98
references.pmid: 1202204
references.citation: Alzheimers Res Ther. 2014 Jul 03;6(4):37
references.pmid: 25024750
references.citation: J Biol Chem. 2012 Dec 7;287(50):41774-86
references.pmid: 23060451
references.citation: Trends Mol Med. 2010 Jun;16(6):287-94
references.pmid: 20537952
references.citation: J Nucl Med. 2015 Apr;56(4):567-74
references.pmid: 25745095
references.citation: J Biol Chem. 2014 Apr 18;289(16):11282-92
references.pmid: 24599963
references.citation: Science. 2012 Mar 23;335(6075):1447-8
references.pmid: 22442467
references.citation: Alzheimers Dement. 2008 Jan;4(1 Suppl 1):S15-20
references.pmid: 18631992
references.citation: J Biol Chem. 2014 Oct 31;289(44):30538-55
references.pmid: 25217640
references.citation: Endocrinology. 2009 May;150(5):2368-75
references.pmid: 19147676
references.citation: Eur J Endocrinol. 2014 Jun;170(6):R253-62
references.pmid: 24616413
references.citation: J Neurosci Methods. 2009 Oct 15;183(2):238-40
references.pmid: 19583979
references.citation: J Nucl Med. 2015 Apr;56(4):560-6
references.pmid: 25745091
references.citation: Science. 1993 Aug 13;261(5123):921-3
references.pmid: 8346443
references.citation: J Alzheimers Dis. 2015;49(2):271-6
references.pmid: 26444777
references.citation: JAMA. 2011 Jan 19;305(3):275-83
references.pmid: 21245183
references.citation: Neurology. 2009 Apr 28;72(17):1487-94
references.pmid: 19339712
references.citation: Neurology. 2014 Mar 25;82(12):1045-50
references.pmid: 24598707
references.citation: Neurology. 1984 Jul;34(7):939-44
references.pmid: 6610841
references.citation: Am J Psychiatry. 1984 Nov;141(11):1356-64
references.pmid: 6496779
references.citation: Alzheimers Dement. 2014 Nov;10(6):861-8
references.pmid: 25217293