Progress in Alzheimer's Disease
Recent Research Results Frustrating for Sufferers of AD
Aug 27, 2008
Alzheimer's disease is an age-related disease resulting in progressive dementia. Initial symptoms, according to the Alzheimer's Association, include forgetting recently learned information, having difficulty completing familiar tasks, having trouble finding or remembering simple words, disorientation, poor judgment, difficulty with abstract thinking, misplacing things, changes in mood including mood swings, personality changes, and loss of initiative. Diagnosing Alzheimer's can be difficult, since other forms of dementia can have similar symptoms. Educated specialists go through a screening procedure to rule out other potential causes. Final diagnosis of Alzheimer's disease technically requires a post-mortem exam to detect characteristic brain pathology associated with the disease.
Pathology
The brains of people with Alzheimer's disease contain extracellular plaques made up of a protein called amyloid beta, and intracellular tangles made up of a protein called tau. How these plaques and tangles are associated with the disease remains a mystery. Many scientists believe these pathological markers cause the disease, and several therapies have been designed based on removing them, particularly the amyloid plaques. Other scientists believe the pathological markers are byproducts of the disease, a sign that something is wrong, but an effect rather than a cause of the disease. In the past year, several therapies aimed at removing amyloid plaques have been tested, with disappointing results.
Recent Trials and Results
The beta amyloid found in the amyloid plaques is a protein that is cut from a larger protein, called the Alzheimer Precursor Protein, or APP. Two drugs were tested recently that were designed to interfere with the production of beta amyloid from APP. The first, a gamma-secretase inhibitor (1), was used in a Phase II trial. The amount of beta amyloid in the plasma was substantially reduced, but no improvement in cognitive function was observed in this 14 week trial. Another gamma secretase inhibitor, Flurizan, was tested in a Phase III trial with disappointing results. This drug had shown promise in a Phase 2 trial (2), but the Phase 3 trial found the drug made no difference in the progression of mild Alzheimer's disease.
A completely different approach to removing amyloid plaques was also tested. Scientists immunized patients to raise antibodies against beta amyloid. The immunization resulted in the clearance of amyloid plaques by the immune system, but this did not result in extended life or prevent neurodegeneration.
The Future
These results are disappointing, because there was great hope that preventing or removing the accumulation of beta amyloid in plaques would improve cognitive function in Alzheimer's patients. It appears that researchers have succeeded in removing the plaques, but this is not enough. Future research will need to focus on other approaches, perhaps in combination with the successful amyloid removal strategies discussed here.
References
(1) Fleisher et al. (2008) "Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease." Archives in Neurology 65, 1031-1038.
(2) Wilcock et al. (2008) '"Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial." Lancet Neurology 7:483-493.
(3) Holmes et al. (2008) "Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo controlled phase 1 trial." Lancet 19:216-223.
