• by Michael Smith, North American Correspondent, MedPage Today

Action Points

Researchers have found new genes that are associated with an increased risk of Alzheimer’s disease.

The three novel genes all appear to play a role in the deposits of amyloid in the brain that characterize Alzheimer’s, as does the only well-established gene that increases the risk for the disease.

Experts hailed the findings as important new data that supports the role of amyloid in the disease, but most cautioned that there is no immediate clinical significance.

The three genes — dubbed CLUPICALM, and CR1 — were reported in two separate studies, published online in Nature Genetics, which used a method called genome-wide association scanning.

One study, led by Julie Williams, PhD, of Cardiff University in the United Kingdom, identified CLUand PICALM as having a significant association with the disease.The other study, led by Philippe Amouyel, MD, PhD, of the Institut Pasteur de Lille in Lille, France, also identified CLU, but instead of PICALM, his team found CR1.

Both studies replicated the 1993 finding that the gene for apolipoprotein E is also significantly associated with the disease. (Three other genes are associated with the rare early-onset form of the disease.)

While no treatments exist for Alzheimer’s, Williams said, “if you took the effect of these genes (CLU and PICALM) out of the population, ideally you could reduce the number of people who develop Alzheimer’s by 20%.”

It is difficult to estimate risk, she added during a press conference, but “these effects are common and could potentially influence disease in a large number of people.”

The British study first analyzed a cohort of 3,941 people with Alzheimer’s and 7,848 healthy controls and found several gene variants that were significantly associated with the risk of the disease, including CLU and PICALM.

Then, in a second cohort of 2,023 cases and 2,340 controls, they replicated the findings and found that only CLU and PICALM remained significant. When the total cohort was analyzed, CLU was significant at P=8.5×10-10 and PICALM at P=1.3×10-9.

The French researchers followed the same pattern, with a slightly smaller initial cohort of 2,032 individuals with Alzheimer’s and 5,328 controls. Their replication group included 3,978 cases and 3,297 controls.

After analysis of the combined data, CLU was significant at P=7.5×10-9 and CR1 was significant at P=3.7×10-9.

The two studies overlapped somewhat — both used a cohort from Belgium — but Amouyel and colleagues said their data remained solid even after they re-examined the data without the Belgians.

Although PICALM may play a role in the development of amyloid deposits, Williams said it may also affect how well neurons function.

In addition, the researcher said, CLU plays a role in inflammation, which many researchers believe to be a secondary effect of the disease.

“Our results suggest the possibility that inflammation may be a primary event in Alzheimer’s disease,” she said.

Exactly how the new genes function remains to be determined, said Michael Owen, MD, PhD, a senior author of the British paper.

The findings may help researchers “triangulate down” to the underlying biological processes that cause Alzheimer’s, he said, but that will take time.

“I don’t think you should expect any treatment to come overnight,” he declared.

Other researchers echoed that view.

“These are landmark studies, and a breakthrough in our understanding of possible pathogenic mechanisms leading to Alzheimer’s disease,” said Scott Turner, MD, PhD, of Georgetown University Hospital in Washington.

But, he added, “there is a ‘large black box’ of missing information between the new genes and any possible treatments that might arise from the findings.

Richard Caselli, MD, of the Mayo Clinic in Scottsdale, Ariz., said the findings raise the possibility of new therapeutic targets but added that, “currently, this information seems to be of greater immediate relevance for researchers than for clinicians or their patients.”

Samuel Gandy, MD, PhD, of Mount Sinai School of Medicine in New York, agreed that “there is no immediate implication for the public — no obvious medication, no new genetic test.”

But he added the findings “will strengthen the rationale for anti-amyloid drugs,” which have so far yielded disappointing results.

Gandy said the implication of inflammation may boost further research on treatments aimed at inflammation, which have also not been successful so far.

In both cases, he said, “this may all be a timing issue. We may just not be starting our interventions anywhere near early enough.”

Rudy Tanzi, PhD, of Boston’s Massachusetts General Hospital, noted that several smaller genetic studies — including one in which he was involved — have found genes associated with Alzheimer’s.

That said, the large scale of these two studies and the fact that they had similar findings suggests the new genes “will likely hold up as real Alzheimer’s genes.”

But he said they appear to have limited effects on risk and are likely to be “bit players in a cast of hundreds” of genes that interact to increase the chance of developing the disease.

Myron Weiner, MD, of the University of Texas Southwestern Medical Center in Dallas, said the studies represent “early basic science” that might one day have clinical relevance.

He added it’s important to remember that the studies only found associations between the genes and the disease “and do not necessarily imply a cause-effect relationship.”

This is republished article. Originally this article was published by https://www.medpagetoday.com