By David Brown
Washington Post Staff Writer
Monday, September 7, 2009; A03
Two European research teams have identified three genes that affect a person's risk of developing Alzheimer's disease, the most common cause of dementia in the elderly.
The new genes appear to have at least as big a role as four others discovered in the last 15 years that are known to play a role in Alzheimer's.
"The message here is that genes are important in Alzheimer's disease . . . and there may be multiple ways of reducing the risk that the genes produce," said Julie Williams, a neuroscientist at Cardiff University in Wales who helped lead one of the teams.
All so-called Alzheimer genes have normal roles in brain physiology; they don't exist solely to cause dementia. Instead, small variations in their DNA alter their function and, through processes only now being uncovered, increase or reduce a person's risk of developing the disease.
Two of the genes described in the new research may be involved in determining the brain's capacity to clear itself of toxic "amyloid" proteins that collect outside neurons, eventually poisoning them.
The most important previously known Alzheimer gene promoted overproduction of amyloid. The new findings suggest that at least two processes -- production of amyloid and its removal -- are involved in the disease.
At least 5 million Americans have Alzheimer's disease. By one estimate, one in seven people age 72 and older has dementia, with Alzheimer's the most common form.
The new findings, reported Sunday in the journal Nature Genetics, will have no immediate consequence in either diagnosis or treatment of the disease. However, they will help illuminate a process that goes on for years or even decades before memory loss, the cardinal symptom of the disease, becomes apparent.
The genes were found through "genome-wide association studies," in which long stretches of DNA are examined for small differences between individuals.
With the advent of cheap and fast DNA sequencing in the last five years, the studies have become a powerful way to uncover genes that make small contributions -- along with environmental influences and personal choice -- to a person's overall risk for such chronic ailments as diabetes, coronary heart disease and depression.
Neuroscientists believe 60 percent to 80 percent of a person's risk of developing Alzheimer's disease is attributable to genes. Knowing which they are and what they do may provide targets for drugs and other interventions.
"Hopefully they will point us to parts of a physiological pathway where we can do some tweaking," said Stephen Snyder, deputy director of the National Institute on Aging, who was not involved in the studies.
In one of them, Williams and her collaborators scanned the genomes of about 4,000 people with Alzheimer's and 7,800 people without it, looking for patterns of variation in half a million locations on the DNA chain. They found three that were far more common in the people with dementia.
One was a variation in the APOE gene -- known since 1993 -- that leads to the overproduction of amyloid protein. The two other genes -- CLU and PICALM -- were new.
CLU appears to be involved in "chaperoning" newly formed amyloid molecules and helping suppress their deposition in the brain.
PICALM, however, seems to play a role in maintaining healthy synapses, the suction cup-like connections nerve cells make with each other to communicate. The loss of synapses is highly correlated with loss of mental function in Alzheimer patients.
A second research group, led by Philippe Amouyel, a neurologist and epidemiologist at the Institut Pasteur de Lille, in France, scanned the genomes of about 2,000 Alzheimer patients and 5,300 control cases.
In addition to APOE and CLU it found another gene, CR1, that is involved in the body's inflammatory response and may specifically play a role in capturing and clearing away amyloid molecules.
Some clinical studies of people with arthritis have found that those taking anti-inflammatory drugs for long periods may have lower rates of Alzheimer's disease.
"Fighting against inflammation may be a clue to fighting against Alzheimer's," Amouyel said, noting that at the moment that is just speculation.
Williams's group had also found CR1, and Amouyel's group had also found PICALM. In each case, however, the frequency of the variations were below the cut-off that defined a "hit." The complementary findings, however, suggest the two genes are truly contributors to a person's Alzheimer risk.
Overall, the effect of APOE is responsible for about 25 percent of Alzheimer cases, CLU 9 percent, PICALM 9 percent and CR1 4 percent. Three other genes are involved in early-onset Alzheimer's, which accounts for about 1 percent of cases.
The importance of various genes in individuals may be quite different from that of the population as a whole.
"The key question is what's in the hand of cards you're dealt, what is the combination of genes you have," said Michael J. Owen, also of Cardiff University, who led the study along with Williams and another scientist, Michael O'Donovan.
The team identified about a dozen other gene "signals" that weren't strong enough to be labeled hits, but that were nevertheless quite strong.
Williams said the team plans to scan 60,000 people next year. She hopes that will provide enough statistical power to identify a second tier of weaker, but still important, genetic variations contributing to a person's Alzheimer risk.