Beta amyloid is a small peptide that results from the processing of the amyloid precursor protein (APP). Beta amyloid has been implicated in the development of Alzheimer’s dementia. Conclusive evidence for beta amyloid as the etiology of Alzheimer’s dementia has been lacking. In addition, several drugs that slow the buildup of amyloid plaque have failed to prevent the progression of cognitive decline that is a hallmark of Alzheimer’s disease. Some researchers have suggested that beta amyloid is an end product of the disease process that ultimately leads to the neurodegeneration. Several gene variants of APP have been found which cause accelerated formation of beta amyloid and faster progression of cognitive decline.
Researchers, lead by Dr. Kari Stefansson, have discovered an APP gene variant that has a very strong protective effect on the development of Alzheimer’s dementia. The results of their study were published in the journal Nature. The researchers identified the gene variant by comparing the genome of 1,795 Icelanders. The gene mutation (or polymorphism) is termed A673T and causes an amino acid substitution at a site where an enzyme called beta secretase 1 cleaves APP into beta amyloid. The polymorphism causes decreased cleavage activity and protects carriers of the mutation from buildup of beta amyloid and cognitive decline. The discovery of an APP gene variant that protects against the development of Alzheimer’s disease adds evidence for the amyloid plaque theory of pathogenesis.
Those individuals who carry the gene variant are five times more likely to reach the age of 85 without having any cognitive functional decline. In addition, they are 50% more likely to reach their 85th year of life compared to individuals without the gene variant. Individuals who are 85 years old and have the gene variant are 81% less likely to develop Alzheimer’s dementia compared to those individuals who do not have the gene variant.
The authors wrote, “The strong protective effect of A673T also provides further proof of principle for the idea that reducing [beta secretase 1] cleavage of APP may protect against Alzheimer’s disease. Furthermore, the fact that the A673T substitution also protects against cognitive decline in the elderly without Alzheimer’s disease provides indirect support for the hypothesis that the pathogenesis of Alzheimer’s disease and normal cognitive decline of the elderly may be shared, at least in part. We therefore propose that Alzheimer’s disease may represent the extreme of the age-related decline in cognitive function”.
This study suggests that blocking beta secretase 1 from cleaving APP can prevent or delay the progression of cognitive decline that leads to Alzheimer’s dementia. Pharmaceutical companies are currently studying several drugs that can inhibit beta secretase 1 and potentially stop or slow the neurodegenerative disorder. If these drugs show promise, future studies should focus on identifying the optimal timing for initiation of treatment.
Thorlakur Jonsson et al. “A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline” Nature 2012; doi: 10.1038/nature11283