Swedish mutation

The Swedish Mutation or Familial Alzheimer's Disease Genetic Mutation is one of the most well known genetic variation that causes early onset familial Alzheimer's Disease.^[1]

History

The mutation was found in 1992 in Florida by Dr. Michael Mullan and Dr. Fiona Crawford working on DNA samples supplied by a group of Swedish researchers led by Dr Lars Lannfelt.

The genetic error causes Alzheimer's Disease to develop in the early 50s for the unfortunate family members who inherit it. On average about half of the children of someone who carries the mutation will inherit it. The mutation is extremely rare - it has only ever been found in two Swedish families and has never been found in the general population in any other countries.

The mutation had important consequences for Alzheimer's Disease research. The mutation occurs in the gene which encodes beta amyloid.^[2] Amyloid is one of the peptides which accumulate in the brains of people with Alzheimer's Disease. A great debate had existed between Alzheimer's Disease researchers about the relevance of amyloid prior to the 1990s - many scientists believed amyloid was a tombstone of the disease and was not critical to the development of the disease. However, because the only difference between the family members who developed Alzheimer's Disease and those that did not in these families was the inheritance of the mutation in the amyloid gene this suggested that the amyloid protein itself could cause the disease. The idea that amyloid could cause the disease influenced scientific research until this day. Many experimental treatments are directed towards lowering amyloid levels in the brain. The other main effect the discovery of the Swedish mutation had was to provide transgenic mouse models of Alzheimer's Disease. Transgenic mice (e.g. Tg2576^[3]) were made which had the Swedish mutation integrated into the normal DNA of mice. As a consequence, the mice over produce amyloid in their brains and although their memories are normal when they are young, as they grow older they accumulate amyloid and begin to lose their memory. In this respect the Swedish mice are similar to the family members who have the disease themselves. They develop memory loss as they age into their fifties although before that age their memories are normal. It is thought that the Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway.^[4]

The Swedish mutation mice are used in hundreds of laboratories all over the world and have contributed to the discovery of many new treatments for Alzheimer's Disease many of which are in clinical trials today.

References

1. Mullan, Michael; Fiona Crawford; Karin Axelman; Henry Houlden; Lena Lilius; Bengt Winblad; Lars Lannfelt (August 1992). "A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N−terminus of Beta-Amyloid". Nature Genetics 1 (5): 345–347. doi:10.1038/ng0892-345. PMID 1302033.
2. , Science Overview: APP and Amyloid Beta in Alzhiemer's
3. "Tg2576".Tg2576
4. "Swedish mutation causes". Nature. Retrieved 6 September 2012.