Rare genetic mutation protective against Alzheimer's disease

A rare genetic mutation, found in about one percent of Icelanders in a recent study, appears to protect  against Alzheimer's disease and age-related cognitive decline. It is the first mutation found to act in this way and could be a target for future drug therapy.

The mutation is located in the amyloid-beta precursor protein (APP) gene and prevents the gene's product from forming the protein plaques that are typical of Alzheimer's disease.

Amyloid-beta plaques have long been the suspected cause of Alzheimer's disease, although researchers lack conclusive evidence; the plaques could in fact be a consequence of other biochemical changes associated with the disease. This study provides strong support that amyloid-beta plaques are the real culprits.

'If amyloid-beta plaques were confirmed as the cause of Alzheimer's, it would bolster efforts to develop drugs that block their formation in order to treat or prevent the ravaging condition', reports an article in Nature News, paraphrasing Dr Kari Stefansson, chief executive of deCODE Genetics in Reykjavik, Iceland, who led the research.

Dr Stefansson added that the study indicated 'that Alzheimer's, and the cognitive decline that awaits all of us if we survive long enough, seems to be mediated through the same mechanism'.

The mutation leads to a slightly different form of APP being produced. The altered section of this APP variant sits next to the site where enzymes split APP into the amyloid-beta proteins that form Alzheimer's plaques. The researchers think the mutation makes it more difficult for the cleaving enzymes, called BACE enzymes, to find the cleavage site.

'We've found the first protective mutation in Alzheimer's disease and provided proof of concept for using BACE inhibitors to treat the disease', Dr Stefansson told the Guardian. 'So if big pharma manages to develop an effective BACE inhibitor, it should probably be put into the drinking water of elderly people'.

Dr Stefansson said that he plans to use his company's platform to investigate rare mutations relevant to other diseases such as ovarian cancer and gout next. 'The rare variants are not going to explain a large amount [of disease], but they are going to provide very key mechanistic insights into how all of this happens', he told Nature News.