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Alzheimers Dement (N Y). 2016 Jun 17;2(2):110-120. doi: 10.1016/j.trci.2016.06.001. eCollection 2016 Jun.

A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects.

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ReXceptor LLC, Cleveland, OH, USA.
C2N Diagnostics LLC, St. Louis, MO, USA.
Department of Neurology, Washington University School of Medicine, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, St. Louis, MO, USA.
Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.



We conducted a phase Ib proof of mechanism trial to determine whether bexarotene (Targretin) increases central nervous system (CNS) apolipoprotein E (apoE) levels and alters Aβ metabolism in normal healthy individuals with the APOE ε3/ε3 genotype.


We used stable isotope labeling kinetics (SILK-ApoE and SILK-Aβ) to measure the effect of bexarotene on the turnover rate of apoE and Aβ peptides and stable isotope spike absolute quantitation (SISAQ) to quantitate their concentrations in the cerebrospinal fluid (CSF). Normal subjects were treated for 3 days with bexarotene (n = 3 women, 3 men, average 32 years old) or placebo (n = 6 women, average 30.2 years old) before administration of C13-leucine and collection of plasma and CSF over the next 48 hours. Bexarotene concentrations in plasma and CSF were also measured.


Oral administration of bexarotene resulted in plasma levels of 1 to 2 μM; however, only low nM levels were found in CSF. Bexarotene increased CSF apoE by 25% but had no effect on metabolism of Aβ peptides.


Bexarotene has poor CNS penetration in normal human subjects. Drug treatment resulted in a modest increase in CSF apoE levels. The absence of an effect on Aβ metabolism is likely reflective of the low CNS levels of bexarotene achieved. This study documents the utility of SILK-ApoE technology in measuring apoE kinetics in humans.


This trial is registered at (NCT02061878).


Alzheimer's disease; Apolipoprotein E; Bexarotene; Retinoid X receptor; β amyloid

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