This may be a naive question, but if amyloid deposition in the brain is a critical factor in AD-related behavioral sequelae, why is it so difficult to induce a behavioral modification of statistical relevance following Aβ vaccination, since reports show a strong amyloid plaque clearance effect?

View all comments by Elliott Mufson

Although the outcome maybe wasn’t as good as had been hoped for, the Phase 2 study on Bapineuzumab, a humanized anti-Aβ monoclonal antibody, provided novel perspectives to the field of immunotherapy against Alzheimer disease. The study enrolled 234 patients with mild to moderate disease, and these were randomly assigned to intravenous antibody infusion or placebo in four dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). After completing the protocol with six infusions, the patients were assessed after 1.5 years. Although no significant differences were found in the primary efficacy analyses, slight differences in cognition could be seen among ApoE ε4 non-carriers. Unfortunately, vasogenic edema occurred in 10 percent of the treated patients and was more frequent in ApoE ε4 carriers who received the higher doses. Ongoing large separate Phase 3 studies on ε4 carriers and ε4 non-carriers, respectively, will be crucial for treatment evaluation—and teach us more about which patients can gain from passive anti-Aβ immunotherapy.

View all comments by Martin Ingelsson

This is a very impressive study. It is the kind of pilot biomarker study that every top investigator dreams of doing, and kudos to the team that did it.

I noticed some 15 percent of AD patients were dropped from entering the trial because the scan showed they did not have sufficient amyloid in the brain. Without dropping these people, the study would likely have had no chance of showing a positive result and might have also exposed more people to risks. This shows the power of PET amyloid imaging to select people who have pathology in order to maximize your chance of a drug effect. Prior to this, we were treating AD patients blindly without knowing how much amyloid they had in their brains, a bit like treating people with a statin without knowing their cholesterol level.

With regard to the bapineuzumab therapy, the magnitude of amyloid clearance seems consistent and real, but at around 20 percent is modest. That is far less than was expected from prior autopsy studies of immunized patients or animal studies which suggested the vaccines might have a much bigger...  Read more

This is a very impressive study. It is the kind of pilot biomarker study that every top investigator dreams of doing, and kudos to the team that did it.

I noticed some 15 percent of AD patients were dropped from entering the trial because the scan showed they did not have sufficient amyloid in the brain. Without dropping these people, the study would likely have had no chance of showing a positive result and might have also exposed more people to risks. This shows the power of PET amyloid imaging to select people who have pathology in order to maximize your chance of a drug effect. Prior to this, we were treating AD patients blindly without knowing how much amyloid they had in their brains, a bit like treating people with a statin without knowing their cholesterol level.

With regard to the bapineuzumab therapy, the magnitude of amyloid clearance seems consistent and real, but at around 20 percent is modest. That is far less than was expected from prior autopsy studies of immunized patients or animal studies which suggested the vaccines might have a much bigger effect. This is a new insight and we might need to lower our expectations. The potential promise with this technology is that we might be able to test how different doses of therapy affect amyloid clearance at an early stage, allowing companies to select the most optimal dose for definitive trials.

Going beyond amyloid, at the end of the day, one can clear all the amyloid in the brain and if the patient does not improve, it still is not a useful therapy. So what's missing is for the field to now show that clearing amyloid eventually leads to a meaningful cognitive and functional benefit for the individual.

Some minor methodologic issues: differences at baseline in cognition and amyloid burden (not unexpected in small studies) between treatment groups add a bit of uncertainty as to interpretation. The method for computing standardized uptake values relative to cerebellum (i.e., the amyloid ratios) varies slightly from one study to another, and one sees different ratios being called normal or abnormal. This makes it hard to compare findings across studies and across tracers. So I think we need head-to-head comparisons and also some standardization of the way one determines a positive from a negative scan.

At HAI and AAN in Toronto, and ICAD in Honolulu, we will see lots of new data on these tracers in terms of cognitive correlates in normals and MCI subjects. I also expect AVID's florbetapir (formerly known as AV-45) will be the first to present validation data from a multicenter autopsy study. Once the validation is complete, this will really jumpstart the use of PET amyloid imaging in secondary and primary prevention trials of both drugs and lifestyle interventions. It will also give us more insight into the role of amyloid in aging and dementia, and allow us to test mechanistic hypotheses.

View all comments by P. Murali Doraiswamy