Going to Biomarker Extremes to Find Rare Alzheimer’s Variants

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From the Alzheimer Research Forum…

5 September 2013. 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.

First author Bruno Benitez and co-authors combined two previously successful approaches. First, they focused on known AD genes, where disease-linked variants were likely: ApoE, amyloid precursor protein (APP), presenilins 1 and 2 (PS1, PS2), progranulin (GRN), and tau (MAPT; see ARF related news story). Second, to raise their chances of finding disease-linked variants with a minimum sample size, the team picked people who were at the extremes of AD biomarkers, those in the top or bottom 15 percent for Aβ, tau or phospho-tau in CSF. The team had previously found a known PSEN1 variant by focusing on people at the highs and lows of amyloid-beta levels (see ARF related news story on Kauwe et al., 2007).

In the current work, the researchers included data and DNA from subjects collected by the Alzheimer’s Disease Research Center (ADRC) at Washington University and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). They selected subjects based only on the CSF biomarkers, without considering case or control status, or how far cases were in their disease progression when the CSF samples were taken. People with low Aβ and high tau levels tended to be cases, Cruchaga said, while those with high amyloid and low tau were more likely to be controls.

Eventually, the researchers plan to sequence DNA from all their subjects, Cruchaga said. But picking out the CSF extremes allowed them to take a shortcut by identifying the people most likely to have interesting genetic variants. “The approach is novel,” commented Rita Guerreiro of University College London in the U.K., who was not involved with the study. She added that few research groups possess both the DNA samples and the CSF data to perform such a project.

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Posted on September 6, 2013
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