Unlikely gene variants work together to raise Alzheimer's risk

October 23, 2013 by Jim Dryden, Washington University School of Medicine in St. Louis
Unlikely gene variants work together to raise Alzheimer’s risk
This PET image of the brain of a patient with Alzheimer’s disease shows a buildup of amyloid deposits (highest amounts in yellow and red) that collect to form senile plaques in patients with the illness. Credit: KNIGHT ALZHEIMER’S DISEASE RESEARCH CENTER

(Medical Xpress)—Studying spinal fluid from people at risk for Alzheimer's disease, researchers at Washington University School of Medicine in St. Louis have found that a gene variation that had not been considered risky actually can increase the chances of developing Alzheimer's disease when it occurs in tandem with another gene variant known to elevate risk.

The findings are available online in the journal Public Library of Science (PLoS) Genetics.

"Up until now, variants in Alzheimer's genes have been classified only as pathogenic or nonpathogenic," said Carlos Cruchaga, PhD, the study's senior author. "Now we know that some of these variants, and particularly some combinations of variants, can be strong for the disease, but most researchers haven't focused much attention on them. We believe our findings may change that."

The investigators sequenced major Alzheimer's genes in four groups of people. The first group was made up of individuals with very high levels of the tau protein in their cerebrospinal fluid, a known risk factor for Alzheimer's disease. Tau is present in the tangles found in the brains of patients with the disorder.

Members of a second group had very low levels of the amyloid-beta protein in their , also a known risk for the disorder. Amyloid-beta aggregates into plaques that dot the brains of Alzheimer's patients.

The researchers also looked at people with very low levels of tau and very high levels of amyloid-beta. Those individuals would be presumed to be at very low risk for Alzheimer's disease.

"We used individuals with extreme levels of these proteins to identify known gene variants linked to Alzheimer's disease," Cruchaga said. "Then we analyzed the association of those variants with risk, and that's when we found gene variations that increase the risk of the disease when they appear alongside other risk variants."

By concentrating on people with very high or low levels of tau or amyloid-beta, Cruchaga's team more easily could locate potential risky gene variants using DNA from fewer subjects than would have been required if they had studied spinal fluid taken from unselected individuals.

Prior to this study, the researchers knew that the ApoE4 gene carried the largest known genetic risk for late-onset, sporadic Alzheimer's disease. Caucasians with two copies of that gene are 10—30 times more likely to develop Alzheimer's by age 75 than those who have ApoE3 or ApoE2 variants instead.

About 40 percent to 65 percent of Alzheimer's patients have at least one copy of ApoE4, but at least one-third of those who eventually develop Alzheimer's don't have the gene, and some people with two copies of ApoE4 never develop the disorder. The findings from this study may help explain why.

Cruchaga's team discovered that when people had one copy of ApoE4 as well as a particular variant in an Alzheimer's gene called PSEN1, their risk for Alzheimer's disease was similar to individuals who had two copies of ApoE4.

"The PSEN1 variant we identified in this study previously had been considered unlikely to contribute to the illness," said Cruchaga, an assistant professor of psychiatry. "But we found that this PSEN1 somehow cooperates with ApoE4 to increase risk."

Cruchaga and his colleagues began the study with DNA from 212 volunteers. They focused only on the six genes previously identified as risk factors for Alzheimer's disease: ApoE, amyloid precursor protein (APP), PS1, PS2, progranulin (GRN) and tau (MAPT). The investigators then identified all of the variants that occurred in each of those genes.

The findings help illustrate how a relatively small number of genetic variations may be able to cause so many cases of Alzheimer's disease.

"Current, large studies of Alzheimer's disease have identified a smaller number of genes than we would have expected," Cruchaga said. "So the question is where is the rest of the signal coming from? And this paper is a clear illustration that interaction between helps contribute to the risk for Alzheimer's disease."

Explore further: Genetic markers ID second Alzheimer's pathway

More information: Benitez, B. et al. The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-4 carriers, PLoS Genetics, vol. 9 (8), Aug. 2013.

Related Stories

Genetic markers ID second Alzheimer's pathway

April 4, 2013
Researchers at Washington University School of Medicine in St. Louis have identified a new set of genetic markers for Alzheimer's that point to a second pathway through which the disease develops.

Major Alzheimer's risk factor linked to red wine target

October 21, 2013
The major genetic risk factor for Alzheimer's disease (AD), present in about two-thirds of people who develop the disease, is ApoE4, the cholesterol-carrying protein that about a quarter of us are born with. But one of the ...

Same genes linked to early- and late-onset Alzheimer's disease

February 1, 2012
The same gene mutations linked to inherited, early-onset Alzheimer's disease have been found in people with the more common late-onset form of the illness.

New Alzheimer's research suggests possible cause: The interaction of proteins in the brain

June 19, 2013
For years, Alzheimer's researchers have focused on two proteins that accumulate in the brains of people with Alzheimer's and may contribute to the disease: plaques made up of the protein amyloid-beta, and tangles of another ...

Key molecular pathways leading to Alzheimer's identified

July 24, 2013
Key molecular pathways that ultimately lead to late-onset Alzheimer's disease, the most common form of the disorder, have been identified by researchers at Columbia University Medical Center (CUMC). The study, which used ...

Gene discovery offers new path for Alzheimer's research

July 9, 2013
A new gene variant has been linked to Alzheimer's disease, and this association is strongest among elderly blacks.

Recommended for you

Anxiety: An early indicator of Alzheimer's disease?

January 12, 2018
A new study suggests an association between elevated amyloid beta levels and the worsening of anxiety symptoms. The findings support the hypothesis that neuropsychiatric symptoms could represent the early manifestation of ...

One of the most promising drugs for Alzheimer's disease fails in clinical trials

January 11, 2018
To the roughly 400 clinical trials that have tested some experimental treatment for Alzheimer's disease and come up short, we can now add three more.

Different disease types associated with distinct amyloid-beta prion strains found in Alzheimer's patients

January 9, 2018
An international team of researchers has found different disease type associations with distinct amyloid-beta prion strains in the brains of dead Alzheimer's patients. In their paper published in Proceedings of the National ...

Advances in brain imaging settle debate over spread of key protein in Alzheimer's

January 5, 2018
Recent advances in brain imaging have enabled scientists to show for the first time that a key protein which causes nerve cell death spreads throughout the brain in Alzheimer's disease - and hence that blocking its spread ...

Molecular mechanism behind HIV-associated dementia revealed

January 5, 2018
For the first time, scientists have identified and inhibited a molecular process that can lead to neurodegeneration in patients with HIV, according to a Northwestern Medicine study published in Nature Communications.

Mice with frequent flier miles advance the Alzheimer's cause

January 4, 2018
Alzheimer's disease wreaks emotional havoc on patients, who are robbed of their memories, their dignity, and their lives. It's financially devastating as well: care for Alzheimer's patients is predicted to top $1 trillion ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.