Going to Biomarker Extremes to Find Rare Alzheimer’s Variants

Researchers have identified potential Alzheimer’s mutations by focusing their attention on people whose biomarkers reach extreme ends of the spectrum. As reported in the August 22 PLoS Genetics, scientists from Washington University in St. Louis, Missouri, found variants both known and novel when they sequenced major AD genes in people with very high or very low amounts of tau and amyloid β in their cerebrospinal fluid (CSF). Led by senior author Carlos Cruchaga, the researchers were surprised to find one of the risk variants was a polymorphism in presenilin 1 (PS1) that had previously been deemed non-pathogenic. When they considered this variant in the context of ApoE4, they found it conferred as much risk as a second copy of that allele. Someone carrying a single copy of both the PS1 variant and ApoE4 has 10 times the risk of someone with wild-type presenilin and no ApoE4, the researchers calculated. As scientists hunt for rare variants, it is important to consider that mutations may still be risk factors even if they exist in people without AD, Cruchaga said.