By David N. Leff
TV commercials that push the three leading cholesterol-lowering pills, Mevacor, Zocor and Lipitor, urge their viewers to "ask your doctor if they are right for you." Conceivably, in the years to come, the sponsors may add a new pitch: "Consult your neurologist to see if these drugs are right for slowing or stopping Alzheimer's disease."
Almost everyone knows that excessive levels of cholesterol in the body are a prime risk factor for atherosclerosis - perpetrator of coronary artery heart disease. As for Alzheimer's disease (AD), the salient risk factors are advancing age and a sawed-off, sinister molecule in the brain, called amyloid-beta peptide 42 (Ab42).
It's a small spin-off from the much larger 700-amino-acid chain called beta-amyloid precursor protein (APP). Ab42 is tarred with the brush of AD's distinguishing hallmark - senile neuritic plaques. Whether these particles, wrapped around the dying neurons of the disease, cause AD or are its consequence remains an open chicken-and-egg question. (See BioWorld Today, Oct. 9, 2000, and March 20, 2001.)
Mevacor (mevastatin) and Zocor (simvastatin) are old-line cholesterol-lowering synthetic statins, widely prescribed for decades. Lipitor (atorvastatin) is a more recent derivative.
In the mid-1990s, two retrospective epidemiological reports, one British, one American, correlated cholesterol-lowering statins with strikingly decreased incidence of AD and dementia.
The current Proceedings of the National Academy of Sciences (PNAS), released on April 10, 2001, carries a report titled "Simvastatin strongly reduces levels of Alzheimer's disease b-amyloid peptides Ab42 and Ab40 in vitro and in vivo." Its senior author is neurobiologist Tobias Hartmann, at the University of Heidelberg, Germany.
On Trail Of Plaque-Forming Peptide
"We knew from those previous experiments," Hartmann told BioWorld Today, "that cholesterol depletion inhibits amyloid-beta production. In this PNAS study we wanted to know if it possible to reduce Ab42 production. We did this in hippocampal neurons [a brain center of cognition] that we prepared from fetal rats, and found it to be the case.
"We wanted to verify this Ab42 decrease also in an animal model of AD." His paper pointed out, "Importantly, guinea pigs are well-established animals for lipid physiology studies. They offer several advantages over mice, because they are more closely related to the human situation. Unlike mice or rats, guinea pigs have the human Ab sequence, and will reflect Ab production by cell types that express endogenous APP levels. The major disadvantage of this model is that amyloid plaque formation cannot be monitored."
"So we fed simvastatin to guinea pigs," Hartmann recounted, "and took weekly samples of cerebrospinal fluid from the animals' brains. We found that after three weeks of treatment, amyloid-beta levels - including Ab42 - were reduced by 50 percent. At that point we stopped the experiment because 50 percent was already highly significant, and more than we expected to get in an animal experiment.
"Zocor and Mevacor are among the top lipid-lowering drugs," Hartmann observed, "but they are pretty old pharmaceuticals now. Their patent protection is to be finished pretty soon. Many companies are producing derivatives of lovastatin. More and more people are using the more modern drugs, such as Lipitor," he went on.
"We decided to do our studies with simvastatin and lovastatin because these substances are brain-penetrant, which many of the later-developed derivatives are not. Just from the hypothesis of their effect on AD, it would be more likely that the brain-penetrant pharmaceutical is more active. But we don't have data on how non-brain-penetrant substances would perform."
To define the mechanism of lipid-lowering drugs, Hartmann suggested, "Statin molecules look a little bit like cholesterol, and the enzyme that makes it thinks it is cholesterol, but it cannot work with this, so it's blocked. Enzymes are sometimes described as keys in keyholes. This would be a key that is broken. It fits in the keyhole, but you can't turn it around, and then you can't use the lock any more. That is the function of statins, and the lock would be the enzyme that produces cholesterol.
"Side effects of statins," Hartmann went on, "are pretty low, and well tolerated by old persons. Some people say their side effects are less than that of aspirin. However," he cautioned, "one side effect to be kept in mind is that statins, by definition, reduce cholesterol levels, in the body's periphery as well as in the brain - something that you may not want. You wouldn't want to prescribe statins with respect to AD for a person whose cholesterol level is already very low. That would be very problematic to do."
Clinical Trials Start In Europe, U.S.
"What we are doing now is trying to solve the $1 million question," Hartmann said. "What is the most detailed picture of the statin's mechanism when it's used specifically to protect from AD? For one thing, the dosage we will have to use is something we do not know for the moment."
He made the point, "The other question is now of course to see in AD clinical trials how effective statins can be. Should you treat early in the disease? Can you treat it when it has already started?" He recalled on this score that "the retrospective study was already using patients who had not yet AD."
"Some of these clinical trials," he observed, "are already being performed in Europe and the U.S. Others are still in the planning stage, or just starting."
One such human study began in August at the Sun Health Research Institute in Sun City, Ariz. It will enroll 120 diagnosed AD patients for treatment with Lipitor, the project's research coordinator, Jean Lopez, told BioWorld Today. "The three-year, on-site, outpatient, placebo-controlled study," she added, "will gauge outcomes by memory and cognitive testing."
"There's one thing that's important to know," Hartmann pointed out. "If you have a high peripheral cholesterol level, the overall risk for getting AD that we know of is only slightly increased. And this may be of interest to people generally. At the moment we cannot make the claim that you should not eat your morning eggs, because as we see it the peripheral cholesterol level is not tightly connected to brain cholesterol levels.
"In light of the blood-brain barrier, there is not so much interchange between the two of them. We do not know yet how much lipid-lowering influences Alzheimer's disease," Hartmann concluded, "but we know from epidemiological studies that your risk is not very much higher if you have more elevated cholesterol numbers than in the average population."