Brain Starvation as We Age Appears to Trigger Alzheimer's

A slow, chronic starvation of the brain as we age appears to be one of the major triggers of a biochemical process that causes some forms of Alzheimer's disease.

A new study from Northwestern University's Feinberg School of Medicine has found when the brain doesn't get enough sugar glucose -- as might occur when cardiovascular disease restricts blood flow in arteries to the brain -- a process is launched that ultimately produces the sticky clumps of protein that appear to be a cause of Alzheimer's.

Robert Vassar, lead author, discovered a key brain protein is altered when the brain has a deficient supply of energy. The altered protein, called elF2alpha, increases the production of an enzyme that, in turn, flips a switch to produce the sticky protein clumps. Vassar worked with human and mice brains in his research.

The study is published in the December 26 issue of the journal Neuron.

"This finding is significant because it suggests that improving blood flow to the brain might be an effective therapeutic approach to prevent or treat Alzheimer's," says Vassar, a professor of cell and molecular biology at the Feinberg School.

A simple preventive strategy people can follow to improve blood flow to the brain is getting exercise, reducing cholesterol and managing hypertension.

"If people start early enough, maybe they can dodge the bullet," Vassar says. For people who already have symptoms, vasodilators, which increase blood flow, may help the delivery of oxygen and glucose to the brain, he added.

Vassar said it also is possible that drugs could be designed to block the elF2alpha protein that begins the formation of the protein clumps, known as amyloid plaques.

An estimated 10 million baby boomers will develop Alzheimer's in their lifetime, according to the Alzheimer's Association. The disease usually begins after age 60, and risk rises with age. The direct and indirect cost of Alzheimer's and other dementias is about $148 billion a year.

The initial trigger of Alzheimer's has long been a mystery.

Ten years ago, it was Vassar who discovered the enzyme, BACE1, that was responsible for making the sticky, fiber-like clumps of protein that form outside neurons and disrupt their ability to send messages.

But the cause of the high levels of the protein in people with the disease has been unknown. Vassar's study now shows that energy deprivation in the brain might be the trigger starting the process that forms plaques in Alzheimer's.

Vassar said his work suggests that Alzheimer's disease may result from a less severe type of energy deprivation than occurs in a stroke. Rather than dying, the brain cells react by increasing BACE1, which may be a protective response in the short term, but harmful in the long term.

"A stroke is a blockage that prevents blood flow and produces cell death in an acute, dramatic event," Vassar says. "What we are talking about here is a slow, insidious process over many years where people have a low level of cardiovascular disease or atherosclerosis in the brain. It's so mild, they don't even notice it, but it has an effect over time because it's producing a chronic reduction in the blood flow."

Vassar says when people reach a certain age, some may get increased levels of the enzymes that cause a build-up of the plaques. "Then they start falling off the cliff," he says.

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Alzheimer's Drug Begins Clinical Trials

A drug based on the design of a Purdue University researcher to treat Alzheimer's disease began the first phase of human clinical trials this week.

"Millions of people suffer from this devastating disease and treatment options are very limited," says Arun Ghosh, the Purdue professor who led the creation of the treatment molecule. "Current drugs manage the symptoms, but this could be the first disease-modifying therapy. It may be able to prevent and reverse the disease."

CoMentis Inc., a biopharmaceutical company based in San Francisco, is initiating the clinical trials of the experimental drug CTS-21166. Ghosh, who has dual appointments in the departments of chemistry and medicinal chemistry, is a scientific co-founder of the company with Jordan Tang, the J.G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation.

The collaborative work of Ghosh and Tang led to the development of a treatment that could intercept and disable the disease at an early stage.

In 2000, Tang identified beta-secretase, a key enzyme in the progression of Alzheimer's that triggers the formation of amyloid plaques in the brain. Various stages in plaque formation produce toxic proteins that harm the brain, causing damage that eventually leads to dementia.
Later that year, Ghosh built a molecule that binds to this key enzyme and inhibits its activity, a beta-secretase inhibitor.

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Newsweek: Alzheimer's and Caregivers

Newsweek Senior Editor Barbara Kantrowitz and Chicago correspondent Karen Springen report on the millions of baby boomers now caring for parents, and in some cases, spouses afflicted with Alzheimer's disease.

Of the 5 million Americans living with Alzheimer's, an estimated 70 percent of them live at home, cared for by family. But the financial and emotional toll on these family members can often become overwhelming. To combat the devastating disease, a growing number of boomers are taking action by increasing public awareness and campaigning for increased research funding. It's estimated that by 2030, Alzheimer's will cost Medicare $400 billion, almost as much as the entire current Medicare budget.

In "A Guide for Caregivers," correspondent Joan Raymond reports on ways to handle the difficult task of being a caregiver to ailing parents. A good place to start is by preparing documents such as a health-care proxy, also called a health-care power of attorney and an advance directive, or a living will. This allows a person to specify medical care and life-support procedures they want.

And in "Insuring Your Future Care," Contributing Editor Jane Bryant Quinn reports on the new ways many baby boomers are looking to prepare for their later years and the different long-term-care options available. Quinn also explores the ways insurers are targeting boomers who might be willingto buy new designer forms of TLC coverage at a younger age.


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Common Pain Medications Do Not Prevent Alzheimer's

Over-the-counter pain medication naproxen and prescription pain reliever celecoxib do not prevent Alzheimer's disease, according to a study published April 25, in the online edition of Neurology, the scientific journal of the American Academy of Neurology. These findings appear to contradict earlier observational studies, which found sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) may have a protective effect against Alzheimer's disease.

The clinical trial, conducted at six dementia research clinics across the United States, involved more than 2,100 people over age 70 with no signs of dementia, but a family history of Alzheimer's disease. The participants were randomly assigned daily doses of naproxen, celecoxib, or placebo for up to four years, but most participants had received the treatments for less than two years.

The study found neither treatment was associated with a reduction in Alzheimer's disease or dementia.

"Although our study was conducted to test the hypothesis that celecoxib or naproxen would reduce the incidence of Alzheimer's disease, these results indicate no such effect, at least within the first few years after treatment begins," says study author Constantine Lyketsos, MD, MHS, with Johns Hopkins Bayview Hospital and Johns Hopkins School of Medicine in Baltimore, Maryland.

The findings appear to be inconsistent with other studies suggesting reduced risk of Alzheimer's disease among people who take NSAIDs over a long period of time. "One possible explanation for this inconsistency is that our findings relate specifically to celecoxib and naproxen, but not to other commonly used NSAIDs, such as ibuprofen. Or the drugs may not prevent the progression of disease in people who have advanced Alzheimer's pathology without symptoms – the very people most likely to develop symptoms within a year or two," says study author John Breitner, MD, with VA Puget Sound Health Care.

"While long-term follow-up of our study's participants is essential, for now we suggest celecoxib and naproxen not be taken to primarily prevent Alzheimer's disease," says Lyketsos.


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O'Connor: Iraq Study Was 'So Out Of My Field'

Retired U.S. Supreme Court Justice Sandra Day O'Connor admits to initially feeling a little out of her element when she was invited to join the Iraq Study Group to offer new alternatives to U.S. involvement in Iraq.

"I wasn't sure I should do it,"she tells Newsweek in an exclusive interview in the current issue. "It was so out of my field of judging. I don't know anything about the military."

President Bush has all but rejected the study group's recommendations but O'Connor is unwilling to criticize Bush.

"There are probably no perfect answers," she tells Assistant Managing Editor Debra Rosenberg in the February 12 issue of Newsweek (on newsstands Monday, February 5).

O'Connor also talks about her decision to retire. In the spring of 2005, with Chief Justice William Rehnquist publicly battling thyroid cancer, the two justices discussed timing. "We talked a little bit,"O'Connor recalls. "I was concerned about whether he had an intention to step down since his plans might have altered my own. It's hard for the nation to grapple with two [retirements] at once," she says. "He indicated he didn't want to step down." So she realized she had to go first.

O'Connor retired so she could spend more time with husband John, battling Alzheimer's disease. O'Connor has had to place her husband at a care facility near their Arizona home.

"It's such a miserable disease. It's so sad. It's so hard. I did the best I could," O'Connor says. "He wants me there all the time."

It's been a difficult transition, says former Sen. Alan Simpson, a family friend. "It's tough to go home at night and no longer have this warm,witty guy there," he says of O'Connor.

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