Study: Zocor May Help Prevent Alzheimer's

Who wouldn't love to find a drug to help prevent or at least delay the onset of Alzheimer's disease? It turns out that one may already exist. Dr. Benjamin Wolozin, professor of pharmacology at Boston University School of Medicine, posted a study this week in the online journal BioMed Central Medicine showing that the cholesterol-lowering drug Zocor (simvastatin) reduced the incidence of both Alzheimer's disease and Parkinson's by about 50 percent in a population of 4.5 million veterans over a three-year period. By comparison, two other statin drugs—Lipitor (atorvastatin) and Mevacor (lovastatin)—showed little or no effect.

Before you rush to your doctor, be aware that it's too early to draw clinical recommendations from the new findings. This was a broad observational study rather than a gold-standard randomized clinical trial, in which all the variables are carefully controlled. "At least one, sometimes two, randomized clinical trials would be required before the FDA would approve marketing the drug for Alzheimer's or dementia," says Dr. Samuel Gandy, chair of the Alzheimer's Association's medical and scientific advisory council. But the new findings added useful information to previous observational studies, which indicated that statins might play a beneficial role in the disease. (Wolozin has a patent on the use of statins in Alzheimer's disease, but no financial ties to Merck, which makes Zocor. The drug is now available as a generic as well as a brand-name pill.)

NEWSWEEK 's Anne Underwood spoke with Wolozin. Excerpts:

NEWSWEEK: There have been studies before looking at the effect of statin drugs on Alzheimer's disease. What's different about this study?
Dr. Benjamin Wolozin:
Two things—the size and incidence. Let me explain. Size is easy. We used the U.S. Department of Veterans’ Affairs database of 4.5 million. Other studies have started with around 5,000 people. If 1 percent of them develop Alzheimer's during the course of the study [50 individuals] and only a few of those 50 were using statins, the numbers don't mean much. With large numbers, you can see who gets the disease and start comparing medications.

How about incidence?
Lots of studies have looked at the progression of Alzheimer's disease in people using statins to see if it helps prevent the disease from getting worse. But we looked at incidence, or the onset of the disease in the first place. Lots of people in the field feel that if we could start medications before people get the disease, we would be much more able to help them. Once you have symptoms, lots of damage has already occurred.

But this study covered only three years—2002 to 2005. Maybe the statins were just delaying the onset of disease, and not actually preventing it.
Absolutely. I strongly doubt statins would prevent people from ever getting the disease. A three-year study doesn't tell you what will happen to people after the study is concluded. In other words, a person who didn't develop the disease during a three-year study between the ages of 65 and 68 could still develop it at 80.  But simply delaying onset could be very important in reducing the costs of Alzheimer's, both personal and financial.

Is this the first study to compare the different statins head-to-head in prevention of Alzheimer's?
Yes, the first to make that explicit comparison.

You included three of the most commonly prescribed statins—Zocor, Lipitor and Mevaor—but not Crestor, which is supposed to be the most powerful of all. Why not?
It's not in the VA database. The VA doesn't always start covering new drugs right away.

So what did you find for the three statins you looked at?
The bottom line is that we saw a 54 percent reduced incidence of Alzheimer's with simvastatin, but not the other two. We also saw a 49 percent reduction of Parkinson's disease. This is the first study to look at Parkinson's disease and statin use in people.

What does this tell us about the role of cholesterol and statins in the two diseases?
Researchers have long thought that one possible way statins might help Alzheimer's was by reducing production of [beta-amyloid, or A-beta, the sticky substance that is a major constituent of the plaques in Alzheimer's brains]. But Parkinson's has nothing to do with A-beta. That suggests that the common mechanism in both may be reduction of inflammation [which is another observed effect of statins and another proposed mechanism for the drugs' beneficial effect on Alzheimer's].

Why would inflammation play a role in both of these?
Have you ever had a cut? Think how the area around the cut gets all red. That's inflammation. Now imagine what happens in the brain when you have Alzheimer's. There is damage to the brain. Around that injured area, you get inflammation. If you can reduce that secondary response, there will be less overall damage.

But if statins all help to reduce inflammation, why did you only see a significant response with Zocor?
We think it's like “Goldilocks and the Three Bears.” It's as if one of the statins is too small, one too big and one just right—except in this case, the difference between them isn't actually size, but potency, and the ability to cross the blood-brain barrier. Mevacor crosses the blood-brain barrier, but it's not strong enough to help reduce inflammation. Lipitor is very good at reducing inflammation, but it doesn't cross the blood-brain barrier very well. Zocor is just right. It crosses the blood-brain barrier and it reduces inflammation.

What are the shortcomings of the study?
There are two classic shortcomings. The first is, you don't know that all the people identified in the database as having Alzheimer's really had it. Alzheimer's can only be diagnosed for certain upon autopsy. In a clinical trial, all the neurologists in the study would perform the same tests and meet the same criteria. In [a "real-world" setting like] the VA, some doctors do it, but others don't. They have 10 patients they have to see in the next hour, and they told their wife they'd be home half an hour ago.

Second, in an epidemiological study, you can never be entirely sure why you're seeing the changes. The study shows an association, but not necessarily cause and effect.

Another weakness, it seems to me, is that most of the people in the VA database are men. What about women?
Yes, totally. Next, we're going to be conducting a study looking at the Kaiser Permanente database of 3 million, which will include women. We're just waiting to get funded.

There isn't enough information yet to start prescribing Zocor specifically for prevention of Alzheimer's, but is there any type of practical information here that people can use?
The upshot is, look at your family history. If you're already taking a statin anyway for reduction of cholesterol and your parents have Alzheimer's, talk to your physician about taking Zocor. On the other hand, if your parents don't have Alzheimer's, but they do have heart disease, you're probably better off on Lipitor, because it's somewhat stronger than Zocor at cholesterol reduction and better at reducing the morbidity of heart disease.

Are there randomized controlled trials in the works?
Two studies will be coming out in the fall, one with Zocor and one with Lipitor, seeing if they can slow progression of the disease. If the drugs help slow progression, they'll probably help with prevention, too. One other thing you should know: I have a patent for the use of statins in Alzheimer's disease. I've never received any money for it, but it's important to disclose these things.

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