Long term effects of Aß42 immunisation in Alzheimer's disease: follow-up of a randomized, placebo-controlled phase I trial
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al.;
Commented by , 18 Aug 2008
Aim of the study
Assess the relation between Aß42 immune response, degree of plaque removal and long term clinical outcomes in patients who participated in a phase 1 study and later came to autopsy.
Methods
Follow-up in September 2006 of patients who participated in a randomized, placebo-controlled phase 1 study of immunization with Aß42 (AN1792, Elan Pharmaceuticals) in 2003. Survival of all 80 participants until severe dementia or death was assessed with a Cox proportional hazard model. Plaques were assessed as percentage of cortex with Aß immunostaining (Aß load) and in terms of characteristic histological features reflecting plaque removal.
Results
9 participants on AN1792 had autopsy. One did not have Alzheimer's disease (AD). In the 8 participants with AD the mean Aß load was lower than in an unimmunized control group matched for age at death (2.1% [SE 0.7] vs 5.1% [SE 0.9]). There was considerable variation in Aß load and degree of plaque removal, the latter found to vary with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). In the whole cohort of 22 patients where follow-up data is available, there was no evidence of improvement of time to severe dementia or to death.
Professor Gauthier's comments
This is an important follow-up to the first attempt at removing amyloid plaques using active immunotherapy. Although the number of subjects is small (9 out of the original 80 participants in the study), it confirms that there is still a 10% error rate in the clinical diagnosis of AD, and that removing plaques can be done effectively using immunotherapy but may not influence the course of AD in its dementia stage.
There is an ongoing debate about the appropriateness of targeting Aß42 accumulation as the main treatment strategy, considering the associated tau, Lewy Body and vascular pathology in AD. There is also accumulating evidence from large scale phase III studies using tramiprosate and tarenflurbil that we need better study designs, outcomes and methods of analysis using genetic and other biological markers to prove benefit in AD.
It is fortunate that the 1st Conference on Clinical Trials on Alzheimer's Disease (CTAD) will take place in Montpellier September 17-19th 2008 to examine many of these issues.