. The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol. 2010 May;67(5):631-3. PubMed.

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  1. The discussion of founder effects of the different FAD mutations is an interesting topic and can increase our knowledge about familial Alzheimer disease, maybe even AD overall.

    This mutation is certainly very old. It is possible that it traveled from Germany to the Volga region and then the U.S. One question one could ask next is whether the phenotype of the disease caused by a given mutation expressed in different environments is different. To do this, it would be necessary to compare phenotypes in larger pedigrees living in separated, well-defined areas.

    Having a family described in Fulda is clear proof that this particular presenilin-2 mutation is still “alive” in Germany. More generally, there are surprisingly few FAD cases with demonstrated mutations in Germany, as compared to Sweden, England, Spain, and Belgium, for example. Whether this is due to relatively little ongoing human AD genetics research, few carriers, or few large pedigrees in Germany remains an open question. An argument toward the second possibility is that for other neurodegenerative diseases (e.g., PD or CADASIL), research groups in Germany have successfully identified pedigrees, meaning the methods and interest seem to be in place. My previous group's search for FAD mutations in German and Swiss families found a presenilin-1 mutation in a family of whom one carrier agreed to participate in neuroimaging research (Mondadori et al., 2006).

    References:

    . Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years. Brain. 2006 Nov;129(Pt 11):2908-22. PubMed.

  2. This is certainly the evidence we all have been waiting for: a "Founder" effect originating in Germany, rather than the Volga River region of Russia where this mutation had been traced to previously. This discovery by Dr. Tom Bird and colleagues at the University of Washington-Seattle may unfold to show that the number of people affected by this mutated gene is larger than previously thought, e.g., that the families from Fulda, Germany, and the American Volga German families with eFAD share the same N141I PSEN2 mutation on an identical haplotypic background. [Editor's note: Gary Miner is prominently featured in Gary Reiswig's book, The Thousand Mile Stare; see ARF related news story.]

    References:
    Familial Alzheimer's Disease: Molecular Genetics & Clinical Perspectives, Edited by Miner, Richter, Blass, Valentine, and Winters-Miner, 1989. Dekker, NY: ISBN 0-8247-8068-X (alk.paper)