If one defines "AD prevention" broadly, then there already has been a recent prevention trial using biomarkers, namely, one led by Bruno Dubois of donepezil in people who met the new diagnostic criteria for prodromal AD. While the trial differs in that it used an approved drug and enrolled symptomatic patients essentially at the MCI stage, it is still worth amending this news story with discussion of that trial (see also ARF related news story). Of particular interest in this context are the endpoints used and how they affect the design of clinical trials in very early Alzheimer's such as A4, which aims at testing anti-amyloid treatments at preclinical stages. Dubois reported a 45 percent reduction in hippocampal atrophy in donepezil-treated patients versus the placebo group, with no changes in cognitive measures. That is, they detected protection when using a surrogate biomarker but not in clinical signs. This means that brain atrophy may be a more sensitive marker of AD-related neurodegeneration than current...  Read more

If one defines "AD prevention" broadly, then there already has been a recent prevention trial using biomarkers, namely, one led by Bruno Dubois of donepezil in people who met the new diagnostic criteria for prodromal AD. While the trial differs in that it used an approved drug and enrolled symptomatic patients essentially at the MCI stage, it is still worth amending this news story with discussion of that trial (see also ARF related news story). Of particular interest in this context are the endpoints used and how they affect the design of clinical trials in very early Alzheimer's such as A4, which aims at testing anti-amyloid treatments at preclinical stages. Dubois reported a 45 percent reduction in hippocampal atrophy in donepezil-treated patients versus the placebo group, with no changes in cognitive measures. That is, they detected protection when using a surrogate biomarker but not in clinical signs. This means that brain atrophy may be a more sensitive marker of AD-related neurodegeneration than current measures of cognitive decline.

However, the trial may not have a clinical application in the short term because regulatory agencies only accept treatments with proven beneficial effects on cognition. This is probably why in the A4 trial, the investigators plan to use very subtle changes in cognitive decline as the main endpoint. An important consequence of this strategy is that the A4 trial will require 300-500 patients per arm and run for three years to achieve enough power. This is an incredibly costly design. For this reason, it is not realistic that the A4 trial becomes the paradigm to test preclinically the currently existing long list of drugs that await trial.

Note that the donepezil trial required approximately 100 patients per arm and ran for a year. One solution is to validate as soon as possible brain atrophy as a biomarker of presymptomatic AD progression by developing longitudinal studies to establish the conversion into MCI of cognitively normal people at high risk according to PET and CSF amyloid-β measurements. This, however, may take many years.

For the time being, another solution, as proposed by Pieter Jelle Visser, is to start screening drugs first in small trials with surrogate markers, and move to larger trials with cognitive endpoints only with successful candidates (Sperling et al., 2011). Looking at time projections, it is probable that by the time the short trials are finished, the regulatory agencies will have accepted surrogate markers to support drug approval for preclinical AD. There will then be no need to follow up in longer trials.

In conclusion, it appears that the right strategy is to combine preclinical trials using surrogate biomarkers as endpoints with longitudinal trials to validate these biomarkers.

View all comments by Elena Galea