. Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity. Hum Mol Genet. 2009 Oct 15;18(20):3987-96. PubMed.

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  1. To further clarify, the two mutations were present in seven out of ~1300 AD families screened. Only two unaffecteds from two different families were mutations carriers (one for each mutation). Thus, we concluded that these mutations are partially penetrant. However, it is still possible that the affection status of either of those those two subjects could change over time. Within the seven families, the two mutations increased risk by 3.5 to ~5-fold. While these O.R.'s are a little greater than that conferred by one copy of ApoE4, these are exceedingly rare familial mutations, not common polymorphisms. Thus, they exert a smaller overall effect on the genetic variance of late-onset AD than ApoE4.

    View all comments by Rudy Tanzi
  2. I wonder what these mutations do to Notch processing/signaling? ADAM10-knockout in mice is embryonic-lethal due the loss of proper Notch function. It's a bit difficult to understand how a human could survive with a 70 percent loss of Notch signaling; but maybe there are compensatory changes in this pathway.

    View all comments by Steve Barger