The new paper raises legitimate questions regarding the potential for artifactual associations emerging from epidemiological studies. My position remains cautiously optimistic because of the faint but positive signal emerging from the Sparks et al. trial (see ARF related news story). Randomized, double-blind placebo-controlled clinical trial data trump epidemiological data every time. The size of the Sparks et al. study (<50 subjects) tempers my enthusiasm, and, like others, I await the results of the large simvastatin clinical trial that is headed by Mary Sano and the ADCS.

View all comments by Samuel Gandy

The cholesterol and statin story in AD has been a never-ending battle since its inception in the late 1980s, and the current paper sends a mixed message. It seems that if the authors exclude the final year of medications from consideration, there is no reduced hazard risk (HR), but if the final year of current statin use is included in the analysis, there is a near significant or significant (for AD with or without vascular factors) reduction in the hazard ratio. One must also consider that an individual who may have taken a statin for, say, 1 month would be included in the "ever statin use." I would suggest the take-home message may be that longer exposure to statins produces a reduced risk of AD later in life.

I am sure that the statin story with regard to treatment of AD will be sorted out by the results of LEADe and CLASP: the two large multicenter trials testing atorvastatin and simvastatin, respectively. The way to determine the effect of statins on prevention of AD (reduced risk) is to directly test for benefit in a double-blind, placebo-controlled prevention trial of...  Read more

The cholesterol and statin story in AD has been a never-ending battle since its inception in the late 1980s, and the current paper sends a mixed message. It seems that if the authors exclude the final year of medications from consideration, there is no reduced hazard risk (HR), but if the final year of current statin use is included in the analysis, there is a near significant or significant (for AD with or without vascular factors) reduction in the hazard ratio. One must also consider that an individual who may have taken a statin for, say, 1 month would be included in the "ever statin use." I would suggest the take-home message may be that longer exposure to statins produces a reduced risk of AD later in life.

I am sure that the statin story with regard to treatment of AD will be sorted out by the results of LEADe and CLASP: the two large multicenter trials testing atorvastatin and simvastatin, respectively. The way to determine the effect of statins on prevention of AD (reduced risk) is to directly test for benefit in a double-blind, placebo-controlled prevention trial of 6-10 years' duration. In advance of expending the time and monies to perform such a prevention trial, I would suggest identifying benefit of statin therapy in delaying the transition from MCI to AD in a double-blind, randomized placebo-controlled MCI treatment trial would strongly support possible success in a prevention trial.

View all comments by Larry Sparks

The recent epidemiological study by Rea and colleagues adds yet more complexity (and confusion) to the issue of statin use and AD risk. It’s difficult to draw any firm conclusions from the study, since the reported outcomes vary so distinctly as a function of analysis parameters. The gold standard will always be double-blind, case-controlled studies, and for good reason. The results from the statin clinical trial(s) in the pipeline will hopefully shed more light on this important issue.

The Rea study does, however, bring to light a couple of general issues (some of which have been discussed previously on Alzforum) that may or may not be resolved in the upcoming prospective clinical trials (e.g., CLASP). If statin use indeed influences AD risk, what duration of use is needed to achieve the effect? I don’t think the “ever use” versus “never use” in the Rea paper is useful in sorting this out. And perhaps more importantly, when do statins need to be taken in order to achieve proposed protection? AD pathology is known to begin years, perhaps decades, prior to cognitive symptoms....  Read more

The recent epidemiological study by Rea and colleagues adds yet more complexity (and confusion) to the issue of statin use and AD risk. It’s difficult to draw any firm conclusions from the study, since the reported outcomes vary so distinctly as a function of analysis parameters. The gold standard will always be double-blind, case-controlled studies, and for good reason. The results from the statin clinical trial(s) in the pipeline will hopefully shed more light on this important issue.

The Rea study does, however, bring to light a couple of general issues (some of which have been discussed previously on Alzforum) that may or may not be resolved in the upcoming prospective clinical trials (e.g., CLASP). If statin use indeed influences AD risk, what duration of use is needed to achieve the effect? I don’t think the “ever use” versus “never use” in the Rea paper is useful in sorting this out. And perhaps more importantly, when do statins need to be taken in order to achieve proposed protection? AD pathology is known to begin years, perhaps decades, prior to cognitive symptoms. Is it mid-life use that protects against future late-life dementia, or will late-life statin use also be of some benefit? By enrolling only demented patients (mild and moderate), the CLASP study will be able to address the issue of efficacy of statin use in preventing clinical progression, but what about preventing or slowing pathologic progression prior to symptoms? This is a much more difficult question to answer and even test. I think it’s still unclear from the human literature whether statins are able to influence the disease process itself or if they merely influence the symptoms. While we’ll take any protective effect we can get, finding an AD treatment that would stop or even slow disease progression at its earliest stages (especially preclinically) is clearly the ultimate goal.

View all comments by Anne Fagan

Recently there has been much debate as to whether statin therapy offers a benefit for Alzheimer disease (AD), and whether statins reduce AD incidence and/or progression remains an open question (Jick et al., 2000; Wolozin et al., 2000; Shepherd et al., 2002; Zandi et al., 2005; Sparks et al., 2005). The prospective cohort study by Rea and colleagues is certainly interesting, and several important factors are brought into consideration, including analysis of the effects of statin use duration, the type of statin used (lipophilicity profile) and patient characteristics. Most importantly, however, this study demonstrates how analysis of the same data set in two different ways can lead to diverging conclusions. Their analysis indicates that antecedent statin use in the population of elderly patients examined was not associated with a lower risk of dementia when primary analysis incorporated a 1-year lag. However, if the data is analyzed in a way similar to that of case-controlled studies, whereby analysis was based on current statin use compared to non-use, without a lag period,...  Read more

Recently there has been much debate as to whether statin therapy offers a benefit for Alzheimer disease (AD), and whether statins reduce AD incidence and/or progression remains an open question (Jick et al., 2000; Wolozin et al., 2000; Shepherd et al., 2002; Zandi et al., 2005; Sparks et al., 2005). The prospective cohort study by Rea and colleagues is certainly interesting, and several important factors are brought into consideration, including analysis of the effects of statin use duration, the type of statin used (lipophilicity profile) and patient characteristics. Most importantly, however, this study demonstrates how analysis of the same data set in two different ways can lead to diverging conclusions. Their analysis indicates that antecedent statin use in the population of elderly patients examined was not associated with a lower risk of dementia when primary analysis incorporated a 1-year lag. However, if the data is analyzed in a way similar to that of case-controlled studies, whereby analysis was based on current statin use compared to non-use, without a lag period, statin use appears somewhat beneficial in protecting against dementia. Thus, this study not only indicates that different results are obtained when a lag period is incorporated into the study design, but also ultimately questions whether statins affect the development of dementia at all.

However, it should be considered that AD is a slow and insidious disease, with abnormal physiological alterations likely preceding the clinical manifestations of the disease by several decades. Indeed, familial AD (FAD) mutations are known to elevate the levels of Aβ42 and thus, while patients with FAD likely overproduce Aβ42 from an early age, clinical symptoms are not typically observed until the third to fifth decades. In the current study, participants had a mean age of 75 years and, as discussed, it may well be the case that statin exposure much earlier in life may be required in order for these drugs to beneficially affect dementia risk. In addition to examining a younger population, it may also be of benefit to extend the lag period; given the insidious nature of AD, a year may not be sufficient for statins to beneficially affect the underlying pathophysiology.

In summary, while there is no doubt that this study provides important insights for the analysis of cohort studies, future prospective studies involving the analysis of a younger population and incorporating longer lag times in the study design would be informative. Ultimately, to provide the definitive answer to the question, are statins protective in AD?, it may be necessary to perform primary prevention studies to determine whether continuous long-term statin use in mid-life (long before the onset of dementia) could prevent or significantly delay AD.

View all comments by Sarah L. Cole
View all comments by Robert Vassar