For almost a decade, cholesterol-lowering statins have seemed one of the most promising classes of drugs in the war against Alzheimer’s. But a series of conflicting and disappointing results, including a just-released study of statin use among elderly Catholic nuns and priests, has clouded the outlook for research in this area.
“There’s certainly a story now to the effect that we all thought we were on the right track, but were we really?” says Samuel Gandy, a clinician at Mount Sinai Medical School who also chairs the National Medical and Scientific Advisory Council of the Alzheimer’s Association.
The statins connection began in the late 1990s, when studies of hospital records—known as “epidemiologic” studies—suggested that people taking the cholesterol-lowering drugs were less likely to develop Alzheimer’s. Although follow-up studies produced conflicting results, the picture seemed to clear last year with a report that linked a strongly reduced incidence of Alzheimer's to only one statin, simvastatin (brand name Zocor).
The study, led by Benjamin Wolozin, a pharmacology professor at Boston University, made use of a Veterans Affairs database with information on 4.5 million patients. Wolozin found that elderly patients in the database who had been taking simvastatin had less than half the incidence of Alzheimer’s compared to those not taking a statin. Wolozin also found that two other statins, atorvastatin and lovastatin, were associated with little or no reduction in disease incidence.
In a way, these results made sense. Simvastatin, says Wolozin, is “the only one of the major statins that gets into the brain for sure.”
Unfortunately, studies of the spinal fluid and the autopsied brains of elderly people who had been taking statins have convinced Wolozin that statins don’t reduce the deposits of amyloid beta protein that appear to be a central factor in Alzheimer’s disease. Tests in animals genetically-engineered to get Alzheimer’s-like amyloid deposits also have shown conflicting results.
“When you look in vivo [in living tissues], you see relatively little evidence that a statin will reduce the amyloid cascade,” Wolozin says. His VA database study also found a reduced incidence of Parkinson’s disease among people taking simvastatin, “which again suggests,” he says, “that if this is real, it’s probably not acting through amyloid beta.”
Along with other researchers, Wolozin believes that simvastatin, in sufficiently high concentration in the brain, can protect neurons by reducing inflammation and stimulating growth factors—two of the many effects statins are known to have besides reducing cholesterol.
Questions of funding
Such subtle effects on the disease process might not be enough. Practically speaking, support for a large and conclusive clinical trial of statins as Alzheimer’s preventatives will require evidence that statins work strongly and directly against the disease—even disease that is already advanced enough to be diagnosed.
“All the new potential Alzheimer’s drugs are being tested on slowing the progression of established disease,” says Gandy, “so if statins don’t work against established disease, it’s going to be very hard to get the enthusiasm and the funding to do a prevention trial.”
Results from two larger trials of statins as treatments for established Alzheimer’s, an NIH-sponsored study of simvastatin and a Pfizer-sponsored study of atorvastatin, will be announced in the next few months. But many Alzheimer’s researchers are pessimistic about statins in this role. “We just have no idea that they work against Alzheimer’s disease,” says David Holtzman, a researcher at the University of Washington.
“I think it’s much easier to have an effect in prevention than on progression,” says Wolozin, “because the disease is not as strongly manifested.” Daniel Pollen, a clinician at the University of Massachusetts, agrees: “You’ve got much more chance to prevent damage than you have to correct it once you start losing synapses and have debris all over the place.” Pollen remains interested in statins as possible Alzheimer’s preventives, although a recent study he helped lead found no significant effect for simvastatin or atorvastatin in reducing levels of amyloid beta and other relevant markers in the cerebrospinal fluid of middle-aged patients with high cholesterol.
Not even prevention?
It may yet be shown that statins, despite some suggestive evidence to the contrary, are of little or no use even as preventives. In a study published in Neurology on January 16, researchers followed a group of 929 elderly Catholic nuns and priests for 12 years, and found that those who used statins did not develop Alzheimer’s at a significantly lower rate. Autopsied brains of those who died also did not show any relation between statin use and reduced Alzheimer’s pathology.
Because relatively few of the subjects were actually diagnosed with Alzheimer’s, the study was too small to be definitive. Researchers also couldn’t separate out the effects of different statins, so it is still possible that simvastatin, for example, had a positive effect that was masked by the ineffectiveness of other statins. (“This is why I chose to stick to examining large databases,” says Wolozin.) But by adding to the bad news about statins, it makes a definitive, large-scale prevention trial even less likely.
No stopping statin use
What is likely, though, is that simvastatin and other statins will continue to be used widely anyway. About 16 million people in the United States alone are taking them to lower cholesterol, and simvastatin, which became available in cheaper generic form in 2006, is on its way to becoming the most popular of the drugs.
Statins moreover have been proven not only to lower LDL cholesterol but also to enhance vascular health.
“If I had elevated cholesterol I would be taking simvastatin, without question,” says Wolozin, who notes that keeping one’s blood vessels healthy and keeping one’s brain healthy are not necessarily separate things. Vascular problems seem to underlie a great deal of organ degeneration, he says, “and the brain is a highly vascularized organ.” Pollen cites a study of subjects with early-stage Alzheimer’s which suggested that “the compounding effect of some vascular changes and neurodegenerative changes is much worse than the effect of either alone.”
There also have been studies suggesting that statins, perhaps through their anti-inflammatory and growth-factor signaling effects, can help to prevent other diseases, including osteoporosis, lung damage from smoking and certain cancers. Statins’ modest but wide-ranging health benefits seem likely to keep them popular, even if they never are found to affect Alzheimer’s.