Engage in healthy behavior

Some everyday actions may help reduce the risk of Alzheimer’s
Mind mystery
Stay mentally active Learn a new skill, read, do crossword puzzles. One study found that older people who engage in mentally stimulating activities were 47 percent less likely to get the disease.
Be social Visit with friends, join a club, stay in touch with family. One study found those who were socially isolated had a 60 percent greater risk of Alzheimer’s.
Stay physically active Exercise or walk at least 30 minutes a day. One study found that sedentary men were twice as likely to develop Alzheimer’s as those who walked two miles per day.
Avoid brain trauma Wear a helmet when riding a bicycle. Use seat belts. The risk of Alzheimer’s increases signifi cantly for those who have suffered severe brain injuries.
Eat right, control your weight, avoid diabetes Choose low-fat, low-cholesterol foods. Eat lots of fruits and vegetables, which contain anti-oxidants. One study linked diabetes with a 65 percent greater risk of developing Alzheimer’s. Another found that women who were signifi cantly overweight at age 70 dramatically increased their risk of getting dementia.
Control your blood pressure, avoid heart disease Don’t smoke. Use diet, exercise or antihypertension drugs to keep blood pressure under control. One study found that those who suffered a stroke were 60 percent more likely to get Alzheimer’s, a risk that appears to be connected to underlying vascular disease.

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Alzheimer's disease appears to have multiple causes, and scientists are slowly unraveling them

By Alice Dembner, Boston Globe Staff  |  March 29, 2005

A century after Alois Alzheimer identified the debilitating dementia that carries his name, scientists are still trying to determine what causes the disease in old age. Their quest takes on increasing urgency, with predictions that unless a cure is found, the number of Americans with the disease will rise from about 4.5 million now to 13 million in 2050.

Many scientists believe that Alzheimer’s results from a complex interplay of environmental factors, lifestyle choices, and genes and proteins gone haywire. But the changes in the brain that characterize the disease develop over decades and also occur in some healthy seniors, making it difficult to sort out the culprits from the bystanders.

Yet, tantalizing tidbits have surfaced in the last few weeks, including discovery of a new genetic mutation that appears to increase the risk of getting Alzheimer’s and new evidence that insulin deficiencies may contribute to deterioration of the brain.

‘‘The pieces are coming together. We’ve got the outline of the puzzle in place, and we’re beginning to see the form,’’ said Stephen Snyder, who oversees research on the causes of Alzheimer’s for the National Institute on Aging. ‘‘It’s probably five or six genes and a dozen proteins that get out of kilter,’’ said Snyder, and certainly not just the sticky clumps of proteins called beta-amyloid plaques that have received the most attention.

In the brain, the disease's hallmarks are those plaques, tangles of another protein called tau, and the progressive death of nerve cells, called neurons, that gradually strip a victim of memory, language, reasoning, and, finally, life.

Mutations in three genes cause early-onset Alzheimer's, the rare form of the disease that strikes people in their 30s, 40s, or 50s. Those altered genes trigger production of too much beta-amyloid. But none appears to be involved in the kind of Alzheimer's that strikes after age 60.

So far, researchers have linked two major genetic changes to old-age Alzheimer's and are on the trail of four or five more. These mutations do not cause the disease, but rather increase the risk of developing it. One, ApoE4, increases the risk of getting the disease three- to four-fold. A second potential gene mutation, called UBQLN-1, was identified this month by Rudy Tanzi, a geneticist at Massachusetts General Hospital. Tanzi, founder of TorreyPines Therapeutics, which is working on Alzheimer's drugs, said he believes it may increase the risk one- to two-fold, but its specific role in the disease has not been determined.

The lead suspect in the search for a cause remains the protein beta-amyloid because of its clear involvement in early onset Alzheimer's and its big presence in Alzheimer's brains.

Tests of an amyloid vaccine in people, which might have proved amyloid's leading role, were halted in 2002 when 18 of 300 subjects developed a potentially fatal brain inflammation. Nevertheless, some participants showed inklings of a positive effect, enough to keep researchers pursuing similar experiments. In addition, antibodies to amyloid reversed memory problems in mice, and cleared out amyloid deposits and then tau.

''It's my feeling that all the cases of Alzheimer's are caused by an imbalance in the accumulation versus removal of the beta-amyloid protein," said Dr. Dennis Selkoe, a leading amyloid researcher who is codirector of the Center for Neurologic Diseases at Brigham and Women's Hospital, and who is a director of Elan Corp. , which is working on amyloid-based treatments.

Much of the amyloid research is shifting away from the big clumps called plaques to focus on smaller clusters that can still be dissolved by the body. The plaques are problematic for researchers because they also occur in people without symptoms of Alzheimer's and do not correlate well with memory problems. Some scientists are now suggesting that plaques, which develop outside the neuron, may be a defensive response, an effect rather than a cause.

The small clusters, on the other hand, correlate closely with memory decline, even before plaques and tangles appear, according to research in mice. The clusters occur inside as well as outside neurons, and may interfere with the ability of neurons to signal each other.

One critic of the amyloid focus, Peter Davies, a professor at Albert Einstein College of Medicine in New York, jokes about the new work on ''the" cause. ''Ten years ago, it was the visible amyloid deposits," he said. ''When everybody realized that didn't work, it became the invisible. It's only one more step before they get it right."

A small group of scientists is instead stalking tau as the lead culprit. In healthy people, tau acts like a scaffolding to support a tube inside neurons that allows movement of nerve impulses. In Alzheimer's, the tau is misshapen and collects in tangles, causing the neuron tube to collapse.

Damage to tau correlates better than amyloid with the severity of Alzheimer's. Research shows that people with mild cognitive impairment, often a precursor to Alzheimer's, have tau tangles but not amyloid plaques in their brains. Other research in mice, however, suggests that tau may need beta-amyloid to do its worst damage in Alzheimer's.

Davies, who like Selkoe has been studying Alzheimer's for decades and is a founding scientist at Applied NeuroSolutions, which is working to develop treatments, said he believes that the disease starts well before tau and amyloid problems appear. He traces the illness back to a number of potential insults -- such as stroke, head injury or problems with insulin -- that he believes trigger nerve cells to try to divide. But unlike other cells, neurons cannot split, and they die in the process of trying, he said. It is this abnormal action of neurons, in this theory, that leads to amyloid plaques and tau tangles.

While the evidence for the cell-cycle theory is still thin, many scientists are investigating possible ''insults" to the brain that might trigger abnormal amyloid and tau, or that might spur worsening of the illness. Stroke, serious head trauma, diabetes and a sedentary lifestyle, for example, are all associated with higher risk of getting Alzheimer's.

''Which is likely to be the originator of the disease?" asks William Thies, vice president of medical and scientific affairs for the national Alzheimer's Association. ''My guess is it's in the life stress."

A paper published this month put insulin's role in the spotlight. Insulin's main role in the body is to help control levels of the sugar that fuels cells. The work at Brown Medical School found abnormally low levels of insulin and insulin growth factors in parts of the brain most affected by Alzheimer's, and that the low levels contributed to the ''brain rotting," said Dr. Suzanne de la Monte, a pathology professor there. Earlier research indicated that insulin helps regulate amyloid and also prevents formation of destructive forms of tau. Studies have also found that people with Type 2 diabetes, in which cells become insensitive to insulin, have a higher risk of developing Alzheimer's.

Other work is focusing on damage caused by destructive oxygen molecules that the body creates when it turns food into energy. Research suggests that this damage and the inflammation it causes can trigger accumulation of beta-amyloid, which can generates more oxygen-related damage. Studies have also found that people who took anti-inflammatory drugs for other reasons had a lower risk of Alzheimer's. But one experiment testing these drugs as treatment for moderate Alzheimer's found no benefit, and a prevention trial in 2,400 healthy adults was halted late last year when the drugs were linked to increased risk of heart attack.

A Seattle researcher, who is testing other possible anti-inflammatory substances, said he isn't sure which comes first, inflammation or accumulation of beta-amyloid and tau. ''That's going to be difficult to determine with certainty," said Dr. Tom Montine, a professor of neuropathology at the University of Washington. ''I view it as a circle. If it's important to the disease process, which one comes first may not be that meaningful."

Alice Dembner can be reached at Dembner@globe.com.