Posted 13 July 2007

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Prevention With Statins: Can the Brain Learn From the Heart?

By Gabrielle Strobel

Cholesterol-lowering statin drugs give people with high blood cholesterol a fair shot at averting a future heart attack. Patients and their doctors across the country got to this place through a 20-year-long series of treatment and prevention trials. This investment was prompted in the early 1980s by biomarker trials in rare, heterozygous, early-onset forms of severe familial cardiovascular disease. This disease is to garden-variety cardiovascular disease what early-onset familial Alzheimer disease (eFAD) is to the more common late-onset Alzheimer disease (LOAD).

The development of statins offers a model for future AD drugs. In the statin story, the disease being targeted is atherosclerosis, which kills patients by causing heart attacks and strokes. Atherosclerosis is a condition in which fatty molecules including cholesterol plaster the walls of blood vessels, eventually blocking blood flow. Researchers linked the disease to high blood cholesterol, and hypothesized that reducing cholesterol would prevent the disease. Scientists then developed drugs to block the body from making so much cholesterol, and measured patients' blood cholesterol levels to determine whether the drugs were working. The FDA was persuaded to accept blood cholesterol readings as a valid surrogate marker for atherosclerosis, that is, as an indirect indicator of the severity of the disease. (A direct disease marker would be measurement of the atherosclerotic plaques, but it is much more convenient and safer to monitor blood cholesterol.)

Statins have a long and storied history complete with criminal indictments, strategic missteps, and false cancer scares. The San Diego-based researcher Daniel Steinberg wrote an upcoming book on this history, called The Cholesterol Wars, and a series of journal articles on the main points is available already (Steinberg, 2006). In a nutshell, the story goes like this: in the late 1960s, the Japanese scientist Akira Endo searched for chemicals that would block cholesterol production. His inspiration was the Scottish scientist Sir Alexander Fleming. Fleming's accidental discovery 40 years earlier that fungi make natural chemicals that halt bacterial growth marked the beginning of the modern antibiotic. If fungi grown in laboratory flasks released chemical agents that inhibit biochemical pathways in bacteria, then the growth broth of fungi might just as well contain other agents that inhibit the pathway of human cholesterol synthesis. By this reasoning, Endo in 1971 discovered the first statin, variously called ML-236B or compactin.

When the time came to put compactin into people for the first time, Endo chose families who had a genetic mutation that caused their cholesterol to build up and led to heart attacks by their thirties. The first inkling of clinical success came in two similar reports on early-onset forms of familial disease, published in 1980 and 1981. These initial studies were tiny, with all of 11 and seven patients in them, respectively. And they said nothing about heart attacks; they merely showed that compactin reduced blood cholesterol by about a third. But the studies were not to be dismissed. "There was no doubt now that, barring the possibility of some unsuspected toxicity showing up in larger and longer clinical trials, this drug and others like it were going to be wonder drugs. Akira Endo had inaugurated the statin era," Steinberg writes. Soon after, large pharmaceutical companies entered the race, and statins eventually proved themselves safe and effective in many different clinical trials, including large primary prevention trials, on a total of 90,000 people.

Scientists note that this drug development story holds three important lessons for AD research.

First, a biomarker benefit shown in small trials of early-onset familial disease held up later in large prevention trials of the more common condition.

Second, the rare form of a disease can be comparable to the common form if they share a core pathway. Most people have high cholesterol for a completely different reason than someone with a hypercholesterolemia mutation. For most of us, it's not that our bodies are genetically driven to overproduce cholesterol; rather, some combination of underlying genetic risk and our diet and lifestyle promote excess cholesterol levels. Despite that difference, the final common pathway—high cholesterol—leads to essentially the same clinical outcome, albeit at a different age. Clearly, in AD it will be some years before we know whether eFAD and LOAD also share a final common pathway, but scientists believe this could well involve a buildup of amyloid and, subsequently, tau pathology in the brain. They emphasize, too, that amyloid and subsequent tau pathology need not be the single cause for LOAD (they probably aren't) in order to offer a decent target for intervention, much like cholesterol is not the only contributor to heart attacks and stroke. It can be one of many causes and still make a therapeutic difference.

Third, an early concern voiced during the development of statin therapy was that cholesterol is a necessary physiological molecule and that curbing its production might do more harm than good, Steinberg writes. The trials put this worry to rest. (It's important to qualify, though, that statins have side effects, as do most drugs, and their net benefit becomes less clear the lower a given person's risk for cardiovascular disease.) Likewise, many AD scientists believe that the amyloid-β protein that is the main constituent of amyloid plaques has a physiological role to play in the body. Clinical trials will have to determine by how much a drug can lower this protein before the body runs into problems.

Scientists won't know for a few more years whether the analogy between the development of statins and AD drugs truly holds water. Can eFAD be a stepping stone to develop a preventive therapy for Alzheimer disease? Given the caveats that keep this vision out of reach for now, the statin analogy serves as a valuable reminder that it can be done.