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https://www.science.org/content/blog-post/another-glp-1-alzheimer-s-trial

Well, here’s another report of a GLP-1 agent being tried in Alzheimer’s patients (after this recent post was written). The last one didn’t show much, so let’s have a look.

In this trial, 204 patients with mild-to-moderate Alzheimer’s were treated with liraglutide (daily injection) versus placebo for one year. The doses started at 0.6mg and worked up to 1.8mg, which is the typical starting dose for diabetes therapy working up to the maximum approved one. The primary outcome was looking for changes in cerebral glucose rate, with secondary endpoints of safety and cognitive assessment changes. That primary endpoint is there because of a good deal of research over the years suggesting that glucose metabolism in Alzheimer’s brain tissue is abnormally low. This may well be linked to insulin resistance in tissues overall, which has led to some characterization of Alzheimer’s as “Type III diabetes” (given the complexities of both conditions, that formulation makes me a bit nervous to tell you the truth). But there are numerous studies in human patients and animal models alike that point towards both those effects, and thus the interest in GLP-1 agonists as potential therapies.

The results are. . .mixed. The primary endpoint first: there was no change in cerebral glucose metabolism between the treated patients and the placebo group. It has already been shown that liraglutide does reach pharmacologically active doses in the brain, so that doesn’t seem to have been the problem here. Given these results, one might want to treat the secondary endpoints with some caution, because the underlying hypothesis for the whole trial seems to have been undermined. At any rate, there does seem to have been an improvement in one of the three cognitive tests systems used (ADAS-Exec) but not in the other two (ADCS-ADL or CDR-SoB). I always wonder what to make of results like this, which are distressingly common in Alzheimer’s trials, and I cannot shake the belief that a robust treatment would not be so dependent on questions being asked and the scoring methods used in the evaluations.

Looking at the individual scores (Figure 3 in the paper), the latter two evaluations do indeed look almost identical to placebo. The ADAS-Exec differences seem driven by a few patients that did indeed score better in the treatment group, versus a slightly larger cohort that scored notably worse in the placebo group: otherwise, the bulk of the individual patient scores overlap in what to me look like similarly-shaped clouds. That’s not to say that these results aren’t real - for example, it could be possible that the disappearance of the longer tail of poor performance as seen the in the placebo group is due to the treatment - but at the very least they do not appear very strong.

The team also looked at volumes of various brain regions via MRI. Volume measures on the hippocampus, entrorhinal cortex, and ventricles did not show any differences between the two groups (all lower), but the temporal lobe showed lower reduction in volume in the treatment group. This was significant (mean and standard error) although the 95% confidence intervals appear to overlap in the individual-patient scores. What this means is unclear; I’m not sure if anyone would have picked the temporal lobe beforehand as the most likely place to see a significant effect.

So there are some effects, although none of them bowl a person over, and (as mentioned) evidence for the main hypothesis that a GLP-1 drug would improve cerebral glucose metabolism did not turn up here at all. I think that the “Type III Diabetes” pitch itself (at least in its strongest and simplest form) is taking some hits here with the results of these GLP-1/Alzheimer’s trials. But so far, Alzheimer’s has not yielded to any simple explanations from any direction.

https://www.science.org/content/blog-post/another-glp-1-alzheimer-s-trial