Although immunisation against the amyloid-β peptide can clear amyloid plaques in the brain, it does not prevent the progressive neurodegeneration associated with Alzheimer's disease. These are the conclusions of authors of an Article in this week's Dementia Special Issue of The Lancet.
A major feature of Alzheimer's disease is accumulation of an amyloid-β peptide in the brain, which leads to formation of plaques. Trials in mice immunised with full-length Aβ (Aβ42) resulted in plaque reduction and an improvement in brain function, but trials in people have so far been disappointing. Professor Clive Holmes, Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, UK and colleagues did a follow up of randomised-placebo controlled phase I trial on Aβ immunisation to determine the long-term effect, if any, of the procedure on patients' brain function.
The study analysed 80 Alzheimer's disease patients who had all been enrolled in a trial of immunisation with Aβ42 (the AN1792 vaccine) in September 2000, with the follow-up study completed by September 2006. 64 patients were given the vaccine and 16 placebo. 20 patients died - 15 from the immunised group, five in the placebo group - before follow-up started. A further 22 - 19 in the immunised group, three in the placebo group, died during follow-up. Nine of the deceased, all from the immunised group, had given permission for post-mortem. Eight of the nine were analysed and found to have lower Aβ load (2.0%) than in controls (5.1%). Although there was considerable variation in Aβ load and degree of plaque removal among immunised participants, the degree of plaque removal correlated with mean antibody response attained during the study period. Seven of the eight immunised patients who underwent post-mortem, including those with virtually complete plaque removal, had severe end-stage dementia before death. Across the whole study group, the researchers found no evidence of improved survival or increased time to severe dementia in the immunised group versus the placebo group.
The authors conclude: "Despite the evidence of disease modification, there is little evidence to suggest that there is any major effect on cognitive function. All but one of the individuals who died during the follow-up phase had clear end-stage dementia before death, including the two individuals with highest mean antibodies to Aβ and almost complete elimination of plaques. These findings imply that progressive neurodegeneration can occur in Alzheimer's disease despite removal of plaques."
In an accompanying Comment, Dr Peter St George-Hyslop, Department of Clinical Neurosciences, University of Cambridge, UK, and Dr John C Morris, Centre for Research in Neurodegenerative Diseases and Toronto Western Hospital, University of Toronto, say: "What are the next steps? Although the current study suggests that anti-Aβ vaccination -- and perhaps other anti-Aβ therapies - may not completely cure symptomatic Alzheimer's disease, removal of the initial motor for the disease might slow progression." They add that further clinical trials which can detect even small changes in disease progression are necessary, and that the future of antiamyloid therapies could see them given in advance as a prophylactic long before the onset of symptoms in people at risk of the disease.
Professor Clive Holmes, Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, UK T) +44 (0) 2380 475216 E) C.Holmes@soton.ac.uk
Dr Peter St George-Hyslop, Department of Clinical Neurosciences, University of Cambridge, UK T) +44 (0) 1223-765542 / +44(0)1223-763369 E) email@example.com