Here’s a follow-up on the news that bexarotene might be useful for Alzheimer’s. Unfortunately, what seems to be happening is what happens almost every time that the word “Alzheimer’s” is mentioned along with a small molecule. As Nature reports here, further studies are delivering puzzling results.
The original work, from the Landreth lab at Case Western, reported lower concentrations of soluble amyloid, memory improvements in impaired rodents, and (quite strikingly), clearance of large amounts of existing amyloid plaque in their brain tissue. Now four separate studies (1, 2, 3, 4) are out in the May 24th issue of Science, and the waters are well muddied. No one has seen the plaque clearance, for one thing. Two groups have noted a lowering of soluble amyloid, though, and one study does report some effects on memory in a mouse model.
So where are we? Here’s Landreth himself on the results:
It was our expectation other people would be able to repeat this,” says Landreth about the results of the studies. “Turns out that wasn’t the case, and we fundamentally don’t understand that.” He suggests that the other groups might have used different drug preparations that altered the concentration of bexarotene in the brain or even changed its biological activity.
In a response published alongside the comment articles, Landreth emphasizes that some of the studies affirm two key conclusions of the original paper: the lowering of soluble β-amyloid levels and the reversal of cognitive deficits. He says that the interest in plaques may even be irrelevant to Alzheimer’s disease.
That last line of thought is a bit dangerous. It was, after all, the plaque clearance that got this work all the attention in the first place, so to claim that it might not be that big a deal once it failed to repeat looks like an exercise in goalpost-shifting. There might be something here, don’t get me wrong. But chasing it down is going to be a long-term effort. It helps, of course, that bexarotene has already been out in clinical practice for a good while, so we already know a lot about it (and the barriers to its use are lower). But there’s no guarantee that it’s the optimum compound for whatever this effect is. We’re in for a long haul. With Alzheimer’s, we’re always in for a long haul, it seems. I wish it weren’t so.