Plaque Removal Fails to Prevent Alzheimer’s
In what is bound to be viewed as a significant setback, the results of vaccine trials aimed at removing amyloid β plaques from the brains of Alzheimer's sufferers, have failed to prevent or reverse dementia. The disappointing news appears in the July 19 edition of The Lancet
Professor Clive Holmes and his team from the Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, UK, found that plaque removal showed some evidence of disease modification but had little significant effect on cognitive function.
The onset and progression of dementia has long been associated with the build up of amyloid plaques and tangles, but it has never been clear whether these cause or result from dementia. The true significance of the build up of plaques in terms of its role on cognitive function, or the potential benefits or relief of symptoms if removed, have also remained something of a mystery.
Vaccine trials began in 2000 with 80 Alzheimer's patients. Sixty four patients received the vaccine and 16 received placebo. By the time of follow-up, eight from the placebo group and 34 from the vaccine group had died.
The experimental vaccine, known as AN1792, did what was expected of it. HealthDay Reporter Steven Reinberg, quotes Holmes as saying, "in some cases there was a virtually complete removal of plaques." However, Holmes went on to say, "Crucially, there was no evidence that patients benefitted from the removal of plaques and even those subjects with virtually complete removal continued to deteriorate and had severe end-stage dementia prior to their death."
Speculating on why plaque removal had no therapeutic effects, Holmes now wonders if just the presence of amyloid β plaques is necessary to initiate, but not to maintain, progressive neurodegeneration? Holmes also notes that the effects of the vaccine was fairly slow and only those who survived 60 months or longer after immunisation showed extensive plaque removal. Another consideration is the role of plaque itself. Holmes points out that a great deal of attention has been paid to oligomeric rather than fibrillar plaques as the cause of neurological dysfunction. Not only might immunisation fail to reduce the concentration of oligomeric amyloid β it could even be increased during the active phase of plaque disintegration. If this is the case, amyloid β in the form of plaques is harmless, possibly even protective, and counterproductive if any attempt is made to remove it.
So what now? Holmes view is that strategies for the treatment of Alzheimer's need to move away from plaque removal to that of plaque prevention. In cases where Alzheimer's is already present he suggests that treatments need to focus on non-plaque therapies.
Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R.W., Bullock, R., Love, S., Neal, J.W., Zotova, E., Nicoll, J.A.R (2008) Long-term effects of A β42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. The Lancet. 372: 216-223.