19 July 2004. One of the field’s biggest hopes for a quick and easy new AD therapy received a punch in the stomach today as the 9th International Conference on Alzheimer’s Disease and Related Disorders got under way in Philadelphia. John Breitner, of the Veterans Affairs Puget Sound Health Care System, Seattle, reported that three new prospective studies—together accounting for a mighty 30,000+ person-years of risk for AD—do not indicate any protection against future development of AD from prior statin use. This new work contradicts the original data linking statin use to reduced AD. What’s more, quite possibly this original data may have been an artifact generated because physicians prescribed statins less frequently to patients with dementia, Breitner charged provocatively. While ongoing treatment trials of statins in AD should continue, this new data weakens the argument in favor of launching costly prevention trials, Breitner argues.
Statins burst on the scene of AD research in the early and mid-1990s, when case-control trials reported that people who took these cholesterol-lowing drugs to prevent heart attacks and strokes appeared to have a lower risk of developing AD, too (e.g., Wolozin et al., 2000; Jick et al., 2000). By now there are seven such studies, and utterly unscientific surveys of researchers in the field (“Are you on it?”) suggest that many cognoscenti take these relatively safe drugs themselves with an eye toward preventing dementia down the line.
As is often the case when small epidemiological studies generate an intriguing new hypothesis, cell and molecular biologists began investigating mechanisms by which these drugs might act in AD. In the case of cholesterol and statins, scientists indeed have established solid in-vitro as well as mouse and guinea pig data showing, for example, that cholesterol and its related forms regulate APP processing. This would suggest that statins might be able to prevent AD, but data on the ability of statins to affect Aβ levels in humans are mixed. Basic science also has described cholesterol- and APP-independent effects statins may exert on processes relevant to AD, such as antiinflammatory or neuroprotective actions that result from the ability of statins to inhibit isoprenylation of a variety of proteins. The genetics front has done its small part by linking a half dozen genes related to cholesterol metabolism to AD, albeit in small studies that are not yet reproduced. Finally, hints of clinical success are on the horizon with small, published trials (Simons et al. 2002, Vega et al, 2004) and more recently a 12-month, controlled trial of atorvastatin conducted by Larry Sparks at the Sun Health Research Center in Arizona. This April, Sparks reported positive data at the Springfield Symposium in Montreal, where they were well received, but the full report of the trial is currently under review. Robustly stemming AD progression with a safe statin drug would be a sensational result, so researchers are eagerly awaiting publication of the full dataset of this trial.
While this good news is trickling in, however, epidemiologists trying to assess the potential of statins in AD more carefully have run into snags. To date, add-on studies looked for cognitive decline in three large, randomized, controlled trials of statins for prevention of cardiovascular disease. They are the Heart Protection Study of simvastatin, the PROSPER trial of pravastatin, and the CRISP trial of cerivastatin. All three failed to show any protection against dementia. Admittedly, Breitner said, the outcome measures used to indicate dementia were crude but even so, at least an inkling of protection clearly should have emerged from trials as large as these. In the Heart Protection Study alone, 20,000 people took drug, or placebo, for five years.
Here now is the disheartening news: Three new prospective, observational studies on AD also found no protective effect against AD. They are the ACT (adult changes in thought) study, the Cardiovascular Health Study, and the Cache County Study; two papers are in press, one is under review, Breitner said.
“The case-control studies were impressive, the prospective data are null. What is going on?” Breitner asked. He suggests the answer lies in the timing of drug exposure and measuring the outcome. The case-control studies were cross-sectional in nature, meaning they took data on exposed, unexposed, and demented cases in the same year. By contrast, the prospective studies asked specifically about antecedent exposure and AD ensuing later. Indeed, to simulate the early case-control studies, the authors took the original data from each of these three new studies and analyzed them as mock cross-sectional studies. Low and behold, now they saw a statistically significant (but entirely spurious) protective effect for statins from the same dataset that yielded a null result when analyzed properly.
The issue boils down to putting sufficient time between exposure to the test agent at hand, and the endpoint measured, i.e., incident AD, when trying to test prevention or risk reduction by that agent. Indeed, in separate addresses on other issues in AD epidemiology, Miia Kivipelto of the University of Kuopio, Finland, Lenore Launer of NIH in Bethesda, and Laura Fratiglioni of the Karolinska Institute in Stockholm, Maryland, all emphasized this same point. The case control studies compared exposed, unexposed, and demented cases in the same year, while in the prospective studies, cases are exposed to the agent under study, then there is a follow-up period of at least a year, and then scientists measure AD incidence. That is a key difference. “We need to time exposure to statins to the critical period of opportunity. We have not found that critical period and have no data in hand right now to do so,” Breitner said.
The major confounding problems in the original studies may have been prescribing bias by physicians, Breitner said. At the time the cross-sectional data was gathered in the early 90s, a doctor who saw a demented patient would have worried about the dementia more than about preventing a heart attack 10 years later. What’s more, at that time statins were new and not yet widely used. So Breitner and colleagues suspect that physicians simply prescribed statins less frequently to people with high cholesterol if they also had dementia. Yet this is not testable, Breitner noted, because today awareness and use of statins have expanded greatly.
In a related presentation, Murali Doraiswamy and colleagues at Duke University in Durham, North Carolina, described data from a small study examining what effect statin use had on hippocampal volume in elderly people with mild cognitive impairment. After two and four years of follow-up, neither hippocampal volume nor white matter was different in people who took statins from those who did not, indicating that statin use over this time period was unable to stem the hippocampal loss that is usually seen as people with MCI progress to AD.
The broader issues underlying this therapeutic approach saw spirited debate between Breitner and Ben Wolozin on the one hand, and Mary Sano, Larry Refolo, and Tobias Hartmann on the other, at the Challenging Views of Alzheimer’s Disease meeting held here in Philadelphia yesterday.—Gabrielle Strobel.