Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"

The goal of this study was to replicate the data by Cramer et al., 2013,  in mice and dogs before considering trials in humans.  The authors tested chronic oral bexarotene treatment  in, Beagles, non transgenic Swiss CD-1 mice and 10-month-old male hAPP/PS1 mice and euthanized the mice 24 hours after the last dose.  In CD-1 mice and dogs  the drug did not affect endogenous levels of soluble Aβx-37, Aβx-38, Aβx-40, and Aβx-42 in brain at different time points, despite the drug’s reaching high concentrations in brain and plasma.  A positive control- JNJ42601572, a known γ-secretase modulator, affected Aβ levels as expected. Similarly, in dogs  the drug had no effect on CSF Aβx-38, Aβx-40, and Aβx-42.   In 10-month-old male hAPP/PS1 mice drug treatment, when compared to vehicle control, did not alter beta amyloid plaque load and plaque number  or soluble Aβ1-40 . ABCA1 levels were significantly up-regulated, demonstrating target engagement. Changes in APP, APP-CTF fragments, or apoE levels were not observed. Thus, previously observed acute and chronic effects of bexarotene on brain Aβ levels were not reproduced.  The cognitive status in chronically treated hAPP/PS1 mice was also tested. Although social recognition memory seemed improved after 14 days of treatment , exploratory tendency was generally reduced in treated versus untreated hAPP/PS1 and control wild-type mice. Bexarotene-treated mice showed significant weight loss, increased irritability during handling and oral gavage, and difficulty breathing, which indicate severe adverse effects of the treatment. These SAEs could have interfered with the execution of behavioral tests.  Thus, although an effect of bexarotene on memory cannot be excluded, the adverse effects of the drug make a definitive conclusion impossible. Given the toxicity of bexarotene, this study clearly and strongly cautions against testing this drug in AD patients at this time.