Fifteen years since the last discovery of its kind, scientists have finally identified a new set of genes that may contribute to Alzheimer's disease.
The three new genes, known as clusterin, complement receptor 1 (CR1) and PICALM, were uncovered by two separate research groups, one in Wales and one in France, who linked the genes to the most common form of the memory disorder, late-onset Alzheimer's — the type that affects patients in their 60s or later and accounts for about 90% of all Alzheimer's cases. The only other gene connected with the condition, apolipoprotein E (ApoE), was identified in 1993; since, researchers have tirelessly hunted for other key genes, knowing that 60% to 80% of the progressive, incurable disease is genetically based.
In the current studies, researchers amassed the largest set of genetic data to date in the study of Alzheimer's, and took advantage of the most recent advances in genetic screening to determine which new genes conferred a high risk of developing the disease. "I think this technique is going to be very valuable, especially for diseases of the brain, where it is very difficult to get in there and see what's going on," says Julie Williams, professor of neuropsychological genetics at the MRC Center of Cardiff University, and one of the authors of the U.K. study, published today in the journal Nature Genetics.
Williams's group collected 16,000 DNA samples from Alzheimer's patients and healthy controls, while the French team, led by Dr. Philippe Amouyel at the Pasteur Institute, gathered more than 7,000 similar samples. Each team worked independently, unaware of the other lab's research, until both happened to present their data at the International Conference on Alzheimer's Disease in Vienna in July. Williams, who was in the audience when Amouyel gave his talk, immediately checked her database on her laptop and found to her delight that her group had identified the same high-risk genes as Amouyel's.
Each group came to their separate conclusions the same way, comparing the genetic activity of their thousands of samples. Williams's team found that among the Alzheimer's patients' samples, certain versions of the genes that coded for clusterin and PICALM were more likely to be active, compared with the controls; in Amouyel's data set, clusterin and CR1 were the two highest ranking genes. While Amouyel's study had also noted PICALM as a high-risk gene of interest and Williams's research had likewise identified CR1, the two groups used different criteria to pinpoint their highest priority genes, leading to the slightly different rankings. (Both groups also found increased activity of the previously discovered gene, ApoE, in their Alzheimer's samples.)
The discoveries mark a significant step forward in Alzheimer's research — until now, three of the four known genes associated with the disease were connected to the rarer, inherited form, which appears in adults as young as 40 or 50. The three additional genes, identified in the new papers, now tip the balance of genetic understanding in favor of the late onset condition that affects a majority of the 5.3 million patients living with the disease in the U.S.
In fact, most healthy people have some version of the three new genes. But their presence alone does not necessarily translate to an elevated risk of Alzheimer's. Each of the genes comes in different forms, or variants, that confer different levels of risk — some variants actually protect against Alzheimer's while others increase the risk. Beyond the effect of specific genes, their interaction with other genes and with an individual's environment may determine how powerfully they contribute to the risk of Alzheimer's. The new research has only identified the relevant genes; the next task for researchers is to figure out which forms of the genes confer how much risk.
"These are common genes, we all have them," Michael Owen, a member of the U.K. team, told reporters at a briefing in London announcing the results. "The key issue is what hand of cards you are dealt, the combination of genes you have that determines your risk."
Based on the prevalence of the new genes and variants in the populations studied, the U.K. and French groups speculate that about 20% to 25% of late-onset Alzheimer's can be explained by ApoE; 8% to 12% by clusterin; and another 3% to 5% by CR1 and PICALM.
Of these genes, two — clusterin and CR1 — are known to interact with the amyloid protein that builds up in the brain of Alzheimer's patients and eventually causes nerve cell death and cognitive problems. Clusterin may be involved in helping to clear away the amyloid that forms in the brain; but another variant of the gene may also allow amyloid to form fibrils, the sticky protein arms that further anchor amyloid plaques to nerve cells, much like a spider web ensnares prey. In late-onset Alzheimer's, it's possible that the body cannot balance these two functions of clusterin. "It may be that the difference between a variant of clusterin that protects from Alzheimer's versus one that has a higher risk is the balance between clearing amyloid versus causing it to form more deposits," says Dr. Alison Goate, an author of the U.K. study and a member of the scientific advisory board of the Alzheimer's Association.
The other gene, CR1, codes for an immune system protein and may be involved in the body's ability to recognize the accumulating plaques of amyloid as foreign. If that's true, says Amouyel, then new treatments based on this approach might be possible. "Maybe there is some metabolic pathway that we can use to stimulate the immune system to work on CR1 to improve the clearance of amyloid," he says. "There may be new pharmacological targets, and this finding opens up ideas."
On the other hand, the discovery of PICALM came as a bit of a surprise. That gene's activity affects the junction between nerve cells, where various neurochemicals work to relay signals from one nerve cell to another. While most of the research attention in Alzheimer's has been on the build up of amyloid protein and tau tangles that strangle nerve function, the identification of PICALM suggests that some part of the disease may have to do with a breakdown in nerve-cell communication at the junctures. "If you had given people a list of genes and said which ones were involved in late onset Alzheimer's disease, PICALM would have been less likely than the others to be picked," says Goate.
But that is precisely the power of studies such as these, say experts. They can identify entirely new and unexpected ways of looking at the disease, and eventually ways to treat it. That's particularly important for Alzheimer's and other diseases that are known to arise largely as the result of genetics. While the three new genes contribute a wealth of knowledge about Alzheimer's, they leave considerable room for the discovery of other key genes — experts agree that there are likely legions of genes that may play a role in the development of any given diseases — and, ultimately, new treatments.