Cholesterol doesn’t entirely deserve its bad reputation. It is essential to the physical integrity and proper functioning of body cells, and is raw material for producing hormones such as estrogen and testosterone. But to be sure, having too much LDL cholesterol in your system increases the risk for heart attacks. Excess LDL accumulates on artery walls as fatty deposits, or plaques. A clot released into the bloodstream from a ruptured plaque can block a coronary artery and cause a heart attack. To prevent that, millions of people are now taking one of the “statin” drugs, which lower the amount of LDL in the blood. These include the top sellers Lipitor (atorvastatin) and Zocor (simvastatin) as well as three others.

In recent years, Alzheimer’s researchers have also turned their attention to cholesterol. They have found intriguing suggestions that high cholesterol raises the risk of developing Alzheimer’s disease—and that treatment with statins may lower that risk. No one can say whether statins will prove safe and effective for treating or preventing Alzheimer’s, but the research is solid enough to justify two large and expensive clinical trials now underway.

Cholesterol on the Brain

Fatty plaques in the arteries (atherosclerosis) causes heart disease. The culprits in Alzheimer’s disease are clumps of a sticky protein, beta-amyloid. All people with Alzheimer’s have these plaques in their brains. In the 1980s, D. Larry Sparks, Ph.D., was the first to find a link between coronary and Alzheimer’s disease. “I’ve been accused of pioneering the field,” says Sparks, now chief of the Roberts Laboratory for Neurodegenerative Disease Research at the Sun Health Research Institute in Sun City, Arizona.

Sparks noticed that older people with coronary artery

disease also had amyloid plaques in their brains. This was an unexpected finding, to say the least. “These amyloid plaques were supposed to only show up in brains of people with Alzheimer’s,” Sparks says. “It was heresy.”

The common link, Sparks believed, was high cholesterol. Everyone agreed that high cholesterol formed artery-choking plaques. Did excess cholesterol in the brain also fuel production of beta-amyloid plaques and lead to Alzheimer’s disease? Sparks proposed that it did, reasoning that the people with plaques in their arteries and their brains were dying of heart disease before they could develop full-blown symptoms of Alzheimer’s.

Subsequent research offered some support for Sparks’s idea. For instance, feeding lots of cholesterol to lab animals increases production of beta-amyloid in the brain. It stood to reason, then, that lowering cholesterol would have the opposite effect: the brain should produce less beta-amyloid. Again, studies with lab animals and cultured brain tissue bore this out.

Epidemiology—the study of patterns of disease in populations—also turned up some tantalizing clues. Research found that people with high cholesterol in midlife are more likely to develop Alzheimer’s disease later. And some studies suggest that people who take statins to prevent heart disease may be less likely to develop Alzheimer’s disease later in life. Other research found no such benefit.

The Statin Solution

So the evidence is a bit mixed and murky at the moment. The important question raised by these studies is this: Does lowering cholesterol with statin drugs combat Alzheimer’s disease? And if it does, how does it work?

Right now, the tentative explanation goes something like this: Brain cells make their own cholesterol. Excess cholesterol in brain cells boosts the conversion of amyloid precursor protein (APP) to both alpha- and beta-amyloid protein. Alpha- and beta-amyloid are very similar, but different in that beta-amyloid forms the toxic plaques implicated in Alzheimer’s disease and alpha-amyloid does not. Sparks says that excess cholesterol in the brain may shift the balance from alpha- to beta-amyloid. The result is relatively more beta-amyloid than alpha, and thus more plaques.

Reducing the level of cholesterol in the brain, then, would squelch production of beta-amyloid. That could delay the age at which healthy people first develop symptoms of Alzheimer’s disease and also slow the mental decline in people already diagnosed. Assuming this all proves to be true, doctors would immediately have a new drug to treat Alzheimer’s disease—a drug already in wide use whose side effects are well understood.

Statins on Trial

Researchers are now probing the neurochemical connections between brain cholesterol and beta-amyloid. In the meantime, Sparks and others have launched clinical trials to find evidence that statins actually help people with Alzheimer’s. Sparks published the results of his pilot study in the May 2005 Archives of Neurology.

Sparks and his colleagues recruited 63 people with mild to moderate Alzheimer’s. Half of them were chosen at random to take 80 mg per day of Lipitor—a relatively high dose that would draw down LDL cholesterol rapidly. The other half took an inactive placebo pill. The people in the study were given a battery of tests every three months for one year to track any changes in their mental status. After 6 months, the people taking statins showed less mental decline. Sparks notes that the improvements emerged only after the statins had begun to reduce cholesterol levels in the blood.

The results of Sparks’s pilot study were strong enough to warrant a larger study, but not to warrant prescribing statins to all Alzheimer’s patients right now. “It’s a proof of concept for the general approach that reducing cholesterol has an impact,” explains Zaven Khachaturian, Ph.D., former director of the Office of Alzheimer’s Research at the National Institutes of Health (NIH) and now an independent consultant on Alzheimer's research with KAI, Inc. in Maryland. “It reinforces the idea that the statin is doing something.” Sparks concurs: “It’s an evolving story. There’s something there. We don’t exactly know what the mechanism is, but there’s something there.”

The larger trials may provide a better answer. The one in which Sparks is participating is funded by Institute for the Study on Aging and Pfizer, Inc., which manufactures and sells Lipitor. The study will involve 600 people who are already taking Pfizer’s Alzheimer’s drug Aricept (donepezil). The idea is to find out if Lipitor and Aricept together slow progression of the disease more so than Aricept alone. The other new trial, funded by the NIH and involving 450 Alzheimer’s patients taking Aricept, will try to determine if the statin drug Zocor slows the progression of Alzheimer’s disease. Pfizer will supply the Aricept for the study.

Back To Basics

Even if the latest trials show a benefit to Alzheimer’s patients, statin manufacturers would still have to run the gauntlet at the U.S. Food and Drug Administration (FDA) to get approval to market statins to treat dementia. That process could take years, many millions of dollars, and perhaps additional studies. Even if approved as an Alzheimer’s treatment, statins would at best slow the progression of the disease. But to individuals and families, that modest benefit would still offer hope in a situation with an otherwise grim outlook. “We could basically extend the quality of their lives a couple of years,” Sparks says.

In the meantime, a successful clinical trial could boost funding for research on the as-yet unclear and unproven connection between cholesterol and dementia. This, says Khachaturian, could prove valuable in other ways. “If it’s shown to be positive, it would really stimulate research and might also attract people from other fields,” such as experts in cholesterol chemistry. “That will make the process go faster.”

Basic research could also reveal a better way to exploit the connection between cholesterol and Alzheimer’s, one more effective than statins. “We’re only just beginning to scratch the surface of this,” Khachaturian says. “The important news here is that studies like Larry Sparks’s are really beginning to point to this line of research as a place we should mine a bit more.”

             -- Copyright © 2005 Memory Loss and the Brain

Further Reading:

“Atorvastatin for the treatment of mild to moderate Alzheimer’s disease,” by D. Larry Sparks and others. (Archives of Neurology, May 2005, Vol. 62,  pp. 753-757.)

"Statins—Cure-all for the brain?” by Til Menge and others. (Nature Reviews—Neuroscience, April 2005, Vol. 6, pp. 325-331.)

"Statins: facts about statins and Alzheimer’s disease.” Fact sheet by the Alzheimer’s Association of Los Angeles. www.alzla.org/treatment/statins.html

Institute for the Study of Aging:

www.aging-institute.org