Another Possible Vaccine for Alzheimer's Disease?

As we discussed in Beating the Dementia Monster, Alzheimer's disease continues to be a black box.  There are so many hypotheses surrounding beta amyloid, tau protein, P. gingivalis, herpes, and others.  When we can finally go to press with the second edition, we will note that cancer research began in earnest in 1913, but Alzheimer's research only got going in the 1980's.  So it's not surprising that we still struggle to get a handle on the basic disease mechanisms. This has implications for progress in both disease prevention and treatment.

In two earlier posts (this one and this one) we considered the possibility of a vaccine for Alzheimer's disease.  The first article considered the possible role of P. gingivalis in the genesis of the disease, and the idea that a vaccine against this pathogen might work.  The second article concerned trials for a vaccine that might work against beta amyloid, training the body to treat it as a foreign intruder.

But what about a vaccine against tau protein?  During the perhaps 15 years of the pre-clinical stage of the disease, abnormal tau is being generated within brain cells.  But at the beginning of the MCI stage, tau is expelled from the cells and spreads throughout the brain.  This produces the tangles that are observed during autopsies.  The spreading tau appears to play a role in the advance of the disease.

This invites another idea for a vaccine.  How about a vaccine that attacks the abnormal tau protein?

At the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually from April 2 to 5, work on such a vaccine got attention.  (We discussed some other interesting takeaways from the conference on April 12 and 13.)

Presenters addressed several initiatives to develop tau vaccines.  In one case clinical trials had not gone well, and others were still trying to get off the drawing board.  But one showed promise in clinical trials. 

The most promising candidate is called "Axon peptide 108 conjugated to KLH" or AADvac1.  Basically the vaccine prompts the generation of antibodies that target one of several abnormal tau proteins.  AADvac1 has completed its phase 2 clinical trial and should -- hopefully -- go into phase 3.  The first two phases of a drug trial look for efficacy of a new drug, but they are first intended to demonstrate safety.  Phase 1 trials are fairly small, and phase 2 will involve more subjects.

In the case of AADvac1, the test subjects had "mild Alzheimer's disease."  (I don't know if that meant they had MCI or were in the mild (first) stage of Alzheimer's dementia.)  After some people dropped out, the phase 2 trial for AADvac1 had 100 subjects on the study drug and 63 on the placebo.  The trial ran for two years.

There were no problems with safety, but does the vaccine work?

Unfortunately, in the two trials there was no evident effect on cognition.  (A subset of younger test subjects may have shown some improved cognition.  "Younger" means ~65-67 years.)  On the other hand, there was pretty good evidence that the process of neurodegeneration was actually slowed.  This was evaluated through changes in blood that are associated with neurodegeneration.

The biotech company Axon Neuroscience plans to move ahead with a phase 3 clinical trial, but they believe they first need to find an international partner.

So what do we make of the fact that the drug slows neurodegeneration but does not appear to improve cognition?  We've found that we can remove amyloid plaques from Alzheimer's brains without improving cognition.  But it appears that cognition will improve somewhat if people stay on a drug long enough after removal of the amyloid to allow healing of the brain.  Will the same apply when removing the abnormal tau protein?