Statins Take On the Brain

They make up one of the most often prescribed classes of pharmaceuticals. Some enthusiastic physicians call them “wonder drugs.” In recent years, these cholesterol-lowering drugs, known as statins, have revolutionized the treatment of cardiovascular disease.

Studies over the past decade have shown that people who have had a heart attack dramatically lower their risk of having a second one by taking statins. Recent data indicate that statins can even lower a person’s chances of suffering an initial heart attack, and the drugs may also prevent strokes. As a result of these findings, statins-which go by such brand names as Lipitor and Zocor-reap enormous profits for the firms selling them.

The fortunes of those companies may just keep on growing.

Scientists are finding that statins may have other unexpected health benefits. They seem to stimulate bone growth, making statins a potential new treatment for osteoporosis and other bone disorders (SN: 1/15/00, p. 41).

Even more provocative, two recent studies looking at the medical outcomes of people who had taken statins for heart disease found hints that the drugs may also have prevented or delayed Alzheimer’s disease. While retrospective studies like these often suggest spurious connections, researchers are excited because they already had indications that blood cholesterol concentrations, or levels, influence the course of the memory-robbing illness.

“Over the years, there’s been a lot of clinical, epidemiological, and more recently, laboratory data that support a link between cholesterol . . . and susceptibility to Alzheimer’s disease,” says Lorenzo Refolo of the Nathan S. Kline Institute for Dementia Research in Orangeburg, N.Y. In statins, “we may have, right at our fingertips, very good drugs for preventing or treating Alzheimer’s disease.”

Statins lower cholesterol by binding to and inhibiting the activity of an enzyme involved in its synthesis, but researchers remain unsure of how statins may thwart Alzheimer’s disease. That uncertainty hasn’t stopped them from pushing ahead. Last fall, Larry Sparks of the Arizona Health Sciences Center in Sun City and his colleagues started a small trial to examine whether a statin arrests progression of the symptoms of Alzheimer’s disease.

Many scientists credit Sparks with first linking cholesterol and Alzheimer’s disease. “Fifteen years ago, I was out, standing in my field, yelling into the darkness. I was alone. In the last 2 years, a lot of people have come around,” notes Sparks.

Sparks might have continued his lonely yelling if not for the two studies last year that associated statin therapy with a reduced risk of Alzheimer’s disease. The first one, spearheaded by Benjamin Wolozin, a cell biologist at the Loyola University Medical Center in Maywood, Ill., appeared in the October 2000 Archives of Neurology.

In analyzing more than 60,000 medical records from three hospitals, Wolozin and his colleagues documented the prevalence of Alzheimer’s disease among elderly patients in general and among the subgroups who had taken statins or other drugs used to treat heart disease or high blood pressure. The investigators found that the prevalence of dementia in patients who took either of two statins-lovastatin or pravastatin-was 30 to 40 percent of that observed in the other patients. Those who had taken another statin called simvastatin, however, showed no anti-Alzheimer’s benefit.

Wolozin’s study “could represent an important breakthrough in the search for a medication that could prevent or arrest the most common form of dementia,” says Robert W. Haley of the University of Texas Southwestern Medical Center in Dallas in the same journal.

The second retrospective study linking statins to a lower risk of Alzheimer’s disease showed up in the Nov. 11, 2000 Lancet. This one, a collaborative effort by David A. Drachman of the University of Massachusetts Medical School in Worcester and Hershel Jick of Boston University Medical School, was what scientists call a case-control study.

Using a database of several million patients from 368 medical practices in the United Kingdom, the researchers identified more than 24,000 people with high cholesterol levels who had taken statins or other cholesterol-lowering drugs, more than 11,000 similar people who took no such drugs, and 25,000 people with normal cholesterol levels and no history of taking cholesterol-lowering drugs.

In those groups, British physicians had diagnosed 284 individuals with dementia. The study didn’t distinguish between different types of dementia, but Alzheimer’s disease is the most common form. Drachman and Jick’s team next identified more than 1,000 control subjects, other people in the study who had no dementia but matched the people with dementia-the cases-in age, sex, and other characteristics.

When the investigators compared the cases and the controls, they found that people who had taken statins faced only about 30 percent the risk of developing dementia as did people with normal cholesterol levels or untreated high cholesterol.

“It looks as if statins may be effective in preventing a very large proportion of dementia,” says Drachman.

The first hints of a connection between cholesterol and Alzheimer’s disease emerged more than a decade ago, when Sparks began examining brain tissue of people who had died with coronary artery disease. He unexpectedly found that deposits of proteins known as amyloids frequently marred these brains, much as these so-called plaques riddle the brains of people with Alzheimer’s disease. Compared with people free of heart disease, people with the illness had four times as much brain amyloid, says Sparks.

Many researchers hold that plaques consisting of an amyloid known as beta-amyloid kill brain cells and thereby cause Alzheimer’s disease. So, Sparks became curious whether some of the established risk factors for heart disease might also lead to the brain disorder.

In an experiment about 8 years ago, he fed rabbits a cholesterol-enriched diet known to cause coronary artery disease in the animals. The diet also increased the amount of brain beta-amyloid, Sparks demonstrated.

What most excited him, however, was finding that returning rabbits to a normal diet reduced the brain beta-amyloid. “If you take the cholesterol away, the [beta-amyloid] goes away,” says Sparks.

Scientists envision several ways that blood cholesterol could influence the amyloid produced by cells in the brain. Consider that the amount of cholesterol in a cell’s membrane governs its thickness and rigidity. The protein from which beta-amyloid originates sits within such cell membranes. Therefore, the cholesterol content of the membrane may make that precursor protein more or less accessible to the enzymes that carve it into beta-amyloid.

Because these enzymes are also membrane-bound, the membrane’s cholesterol content could also govern their activity.

Moreover, cholesterol appears to influence the production of a protein called apolipoprotein E (APOE), one form of which is a risk factor for both heart disease and Alzheimer’s disease. Feeding mice a cholesterol-rich diet increases the amount of APOE in their brains, notes Refolo. While APOE’s role in Alzheimer’s disease remains unclear, scientists suspect that the various forms of the protein have different efficiencies in clearing beta-amyloid from the brain.

Confirming a connection between cholesterol and beta-amyloid, Refolo recently extended Sparks’ work on rabbits to genetically engineered mice that are widely used as an animal model of Alzheimer’s disease. Last summer, Refolo and his colleagues reported in the August 2000 Neurobiology of Disease that a cholesterol-rich diet increased the size and number of beta-amyloid plaques in the rodents’ brains.

According to unpublished work he presented last summer at the World’s Alzheimer’s Congress in Washington, D.C., Refolo also found that a cholesterol-lowering drug dramatically reduced formation of beta-amyloid in mouse brains. Refolo used a drug that’s not a statin but binds to and inhibits the activity of an enzyme for cholesterol synthesis. He now plans to repeat the study using a statin.

Refolo’s work suggests a direct correlation between the concentration of cholesterol in the blood and the amount of beta-amyloid littering the brain. Yet it’s far from settled that statins protect the brain by lowering a person’s cholesterol level. In Drachman’s study, for example, people taking cholesterol-lowering drugs other than statins didn’t enjoy a significantly reduced risk of dementia.

“It might very well be that statins do not work totally by their cholesterol-lowering ability,” acknowledges Refolo.

Indeed, the issue of what else statins do in the body is drawing new attention. “There’s a lot of discussion on the mechanisms underlying statins’ effects,” says Gerard J. Blauw of the Leiden University Medical Center in the Netherlands, who’s studied how statins may prevent strokes.

A few reports hint that the drugs modulate immune responses, perhaps by dampening inflammation. A large body of research implicates inflammation in the brain-and in the vasculature that supplies it with blood-as a contributing factor in Alzheimer’s disease, notes Michael J. Mullan of the University of South Florida in South Tampa. In inflamed brain areas, for example, the abnormal activation of brain immune cells called microglia may play an important role in the disorder.

Mullan’s colleague Daniel Paris has shown that both beta-amyloid and cholesterol can, in test-tube experiments, stimulate an inflammatory response within blood vessels and cause them to constrict. Statins block both those effects and do so independently of the drug’s inhibition of cholesterol synthesis, says Paris.

When it comes to stopping Alzheimer’s disease, suggests Mullan, “statins may have a dual role. They may be able to oppose the immediate effects of both [beta-amyloid] and cholesterol in stimulating inflammation in the vasculature . . . and they may be able to block the inflammatory role of [beta-amyloid] and cholesterol on microglia.”

Statins “could simply be improving cerebral vasculature,” agrees Drachman, who notes that the drugs can directly enhance the function of endothelial cells, which make up the lining of blood vessels.

While the statins’ actions beyond their effects on cholesterol do intrigue investigators, research into those effects is in its infancy. “There’s no evidence that these effects are clinically important,” cautions Blauw.

Some scientists argue that they don’t need to know potential mechanisms before they try to confirm that statins thwart Alzheimer’s disease. Since the statins have a well-established safety record, only rarely causing serious side effects, these researchers are ready to test the drugs against Alzheimer’s disease.

In a trial that started last fall, 60 people with mild-to-moderate Alzheimer’s disease will take a dose of statin every day for 3 years, and 60 similar people will take a placebo pill.

Sparks and his team have taken a stand with their choice of a statin for the trial. They’re administering one called atorvastatin, largely because, unlike some other statins, it doesn’t seem to cross from the bloodstream into the brain. Sparks argues that lowering cholesterol concentrations in blood alone permits excess brain cholesterol to seep back into the blood.

In his view, a statin that enters the brain could stop needed cholesterol synthesis there and harm nerve cells. “It’s ill-advised to treat an Alzheimer’s patient with a statin that crosses the blood-brain barrier,” contends Sparks.

Not all scientists agree. If statins work by reducing inflammation and not by lowering cholesterol levels, for example, a statin that gets into the brain might be key to success against Alzheimer’s.

Even if the results of the new trial prove disappointing in stopping the progress of dementia that won’t rule out atorvastatin or other statins for preventing Alzheimer’s disease, notes Sparks. The patients enrolled in the current study may already be too advanced in their dementia for the drugs to help, he explains.

Sparks’ study may also prove too small to produce statistically convincing results, suggest some scientists. Another statin study under way in Europe, will monitor nearly 6,000 people’s responses to pravastatin or a placebo pill given daily for more than 3 years.

This effort, known as the Prospective Study of Pravastatin in the Elderly at Risk study (PROSPER), follows up a finding several years ago by Blauw and his colleagues suggesting that pravastatin may prevent strokes. The main goal of PROSPER is to confirm that result. But since a series of small, undetected strokes may be the cause of many cases of dementia, PROSPER investigators will also monitor the cognitive function of their study’s participants. All are 70 or older and have coronary artery disease or are at high risk for it.

If a statin does forestall decline in mental function in some volunteers, the researchers will look to see whether the drug prevented minor strokes or reduced inflammation in the brain.

In contrast to Spark’s therapeutic trial, PROSPER should offer the first evidence from a prospective trial indicating whether statins can prevent mental decline, says Blauw. He cautions that the study won’t resolve whether physicians should prescribe the drugs to avert Alzheimer’s disease.

Even if PROSPER reveals that statins reduce dementia, investigators will need to conduct additional trials to address Alzheimer’s disease specifically and to see whether the drugs work in patient populations that are younger and not at high risk for heart disease.

Summarizing current data on statins and Alzheimer’s disease, Drachman recalls the first hints that aspirin taken regularly could protect against heart disease.

It took more than a decade to confirm aspirin’s effect, he notes, and investigators continue to debate how much aspirin a person should take. While statins clearly represent a promising lead for preventing Alzheimer’s disease, it will take some years to confirm that benefit, says Drachman.