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Risk Factor:
Risk Factor Type: Medications
Current Understanding:
The tables below summarize results from a series of observational studies of statin use in relation to AD dementia risk. Although there is significant heterogeneity of findings across studies, there is currently insufficient evidence to conclude that statin use affects risk of Alzheimer’s disease or all cause dementia. While research considering statin use at or within one year of the time of dementia consistently reports protective associations between statin use and Alzheimer’s disease, such studies are particularly susceptible to bias from and reverse causation (given that persons with cognitive deterioration may be less likely to be prescribed or continue taking a statin). Conversely, consistent with the results of randomized clinical trials, studies that tracked AD dementia risk over several years following assessment of statin use at a set “baseline” individually and collectively report no association. However, the relation between statin use and Alzheimer’s disease in the general population remains an open question. Most of these studies were conducted prior to the wide adoption of statin use for primary prevention. They are limited by small numbers of statin users and could not consider the impact of use of statins in midlife or sustained statin use from midlife to late life on dementia risk. Regardless, statins have demonstrated benefits on cardiovascular disease and mortality and are therefore are increasingly widely recommended for both primary and secondary prevention of cardiovascular events and associated mortality. For a more in-depth discussion of these studies considering the association between statin use and AD, please see the Discussion. An expanded examination of the relation between statins and dementia or cognitive decline can be found in the related published review, Power MC, Weuve J, Sharrett AR, Blacker D, Gottesman RF (Nature Reviews Neurology 2015, doi:10.1038/nrneurol.2015.35.
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Risk Factor Overview

Power MC, Goonesekera S, Kim IY, Weuve J, Blacker D. “Statin Use.” The AlzRisk Database. Alzheimer Research Forum. Available at: http://www.alzrisk.org. Accessed [date of access].*

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Introduction

The tables on the Risk Factor Overview present results from a series of observational studies on statin use in relation to Alzheimer disease (AD) dementia risk. Considering these and related data, there is currently insufficient evidence to conclude that statin use affects risk of Alzheimer’s disease or all cause dementia. Many studies considered statin use at or within one year of the time that participants were assessed for dementia. These studies consistently reported protective associations between statin use and AD dementia, but they are particularly susceptible to bias from reverse causation (given that persons with cognitive deterioration may be less likely to be prescribed or continue taking a statin). Conversely, consistent with the results of randomized clinical trials, studies that tracked AD dementia risk over several years following assessment of statin use at a set “baseline” individually and collectively reported no association. Below, we provide an overview of why it has been hypothesized that statins protect against AD and other dementias; we discuss the methodological considerations and challenges of observational research on the relation between statins and dementia, including an in-depth discussion of the potential for and likelihood of systematic bias; and we provide additional context through a brief review of related literature on statin use and all-cause dementia and cognitive decline, including results from randomized clinical trials. An expanded examination of the relation between statins and dementia or cognitive decline can be found in the related published review, Power MC, Weuve J, Sharrett AR, Blacker D, Gottesman RF (Nature Reviews Neurology 2015, doi:10.1038/nrneurol.2015.35.


Potential Mechanisms of Action

Statins, a class of drugs that inhibit the enzyme HMG-CoA reductase, are used clinically for the prevention of cardiovascular events and associated mortality, as primary prevention for high-risk individuals and as secondary prevention for those with previous cardiovascular events. Although statin use has been associated with acute adverse cognitive effects, including confusion and ill-defined memory loss, leading to a 2012 change in the labeling for statins, such effects appear to occur shortly after initiation of statins, reverse with discontinuation of the medication, and are not associated with dementia (United States Food and Drug Administration, 2012). Hypotheses about the effect of statins on dementia risk actually posit a benefit of statin use, with statin users expected to have lower risk of Alzheimer’s disease or other dementias.

Statins reduce circulating cholesterol levels. As elevated cholesterol levels in midlife appear to be related to late-life risk of dementia (Anstey, Lipnicki, & Low, 2008), statin use may reduce dementia risk through its effects on cholesterol and consequent effects on cerebrovascular disease, which in turn increases the risk of having AD dementia. Consistent with a primarily vascular effect, statin use does not appear to be associated with cortical volume, a marker of brain atrophy (Manschot et al., 2007), but does appear to be associated with white matter hyperintensity volume and progression (Manschot et al., 2007; Mok et al., 2009), typically an indicator of damage to small blood vessels in the brain. Lipophilic statins, which can cross the blood-brain barrier, do appear to affect brain cholesterol metabolism (Carlsson et al., 2012; Locatelli et al., 2002; Lutjohann & Von Bergmann, 2003; Serrano-Pozo et al., 2010; Vega et al., 2003), at least in the short term (Evans et al., 2009). However, the relevance of these effects on risk of AD dementia remains unknown. Statin use has also been shown to increase cerebral blood flow over a 4 month pilot trial (Carlsson et al., 2012).

Beyond these vascular effects, statins may impact dementia risk in other ways. Statins appear to influence amyloid-beta metabolism and deposition in animal and cell models of AD (Hoglund & Blennow, 2007; Miida, Takahashi, & Ikeuchi, 2007); however, there is little evidence indicating similar effects on amyloid beta in humans (Fassbender et al., 2002; Hoglund et al., 2005; Lutjohann & Von Bergmann, 2003; Riekse et al., 2006; Serrano-Pozo et al., 2010). There is also some evidence linking statin use to cerebrospinal fluid (CSF) levels of phosphorylated tau (Pollen et al., 2010; Riekse et al., 2006; Serrano-Pozo et al., 2010) and neurofibrillary tangle burden at autopsy (Li et al., 2007), suggesting a potential impact of statins on tau AD pathology. Statins also appear to have a variety of other effects that may also influence dementia risk, including effects on coagulation, nitric oxide availability, as well as anti-oxidant and anti-inflammatory properties (Bifulco, Malfitano, & Marasco, 2008; Jain & Ridker, 2005; Miida et al., 2007).


Methodological Issues

Exposure Assessment

The studies reviewed here typically assessed statin use through use of medication inventories at the time of scheduled study visits or linkage to prescription databases. Statins were almost uniformly considered as a class, with usage characterized with a simple yes or no. Few studies considered duration or timing of use, despite potentially important implications for risk of AD dementia. Similarly, few studies differentiated among specific statins, which vary in their ability to cross the blood-brain barrier, and those that did were limited by small sample sizes.

The studies reviewed here can be classified broadly in terms of how they treated exposure status (yes/no) analytically. One group of studies, summarized in Tables 2 and AlzRisk review of diabetes), a survivor bias could lower the estimated association between statin use and AD dementia (i.e., overstate protection or underestimate harm). Adjusting for such risk factors would avert this source of bias but many studies reviewed did not fully account for all indications for statin use in their design or multivariable-adjusted analyses.

Period Effects and Confounding by Indication

Statins were first approved for use in the United States in 1987. According to the Centers for Disease Control, statin use among U.S. adults over the age of 45 rose from 2% in 1988-1994 to 25% in 2005-2008; with even higher prevalence among older individuals (National Center for Health Statistics, 2011). This marked growth in use is due, in part, to expanding indications for statin use. In 2002, the Third Adult Treatment Panel (ATPIII) of the National Cholesterol Education Program (NCEP) published guidelines for the treatment of hypercholesterolemia. These guidelines included an algorithm combining low density lipoprotein (LDL) levels, number of cardiovascular risk factors, and predicted risk of a coronary heart disease event to determine if lipid-lowering therapy (typically statin use) was warranted, in addition to or simultaneously with lifestyle changes (National Cholesterol Education Program, 2002). In 2004, the Coordinating Committee of the NCEP suggested modifications to these recommendations based on new evidence from five large clinical trials of statin use, calling for lower LDL target levels for high risk individuals (Grundy et al., 2004), with the implication that even more people had indications for statin use. In 2013, the American College of Cardiology and the American Heart Association (ACC-AHA) published a new set of U.S. guidelines for the management of cholesterol, further expanding the indication pool (Stone et al., 2013). These guidelines abandon reliance on targets for LDL, instead suggesting statin use for primary prevention among those with diabetes or high calculated risk of cardiovascular events and for secondary prevention among persons with a previous cardiovascular event. These changes result in significant increases in the number of persons with an indication for statin use. Under the ATP III guidelines, an estimated 37.5% of U.S. adults between the ages of 40 and 75 have an indication for statin use, compared with 48.6% under the ACC-AHA guidelines (Stone et al., 2013). The marked increase primarily reflects recommendations for expanded use of statins for primary prevention of cardiovascular disease, especially among those between the ages of 60 and 75, of whom over 77% are estimated to be recommended for statin use under the new guidelines (Pencina et al.).

This expansion of use over time has implications for the epidemiologic study of statins. First, the baseline examination for the vast majority of studies included in our tables occurred in the early 1990s, shortly after the introduction of statins and prior to both the ATPIII and ACA-AHA recommendations. During this time period, statin use was relatively rare. As such, the effect estimates in the tables are based on an extremely small number of statin users, and an even smaller number of statin users who subsequently developed AD dementia. For example, Zandi et al. (2005) reported associations based on 102 cases of AD dementia, of whom only 4 were statin users at baseline. Of studies that reported the number of AD dementia cases by statin use, the vast majority were based upon fewer than 20 persons with both statin use and AD dementia. The possibility of chance positive findings (which are more likely to be published than null findings from small samples) or dramatic distortion of study results due to confounding bias is greater with such small numbers. Second, the complexity of changing prescribing behavior will lead to changes in the sources of confounding over time, and--even if earlier results are unbiased—in how well these results generalize to subsequent populations of persons meeting relaxed thresholds for use.

Interestingly, the studies reviewed here did not restrict the sample population to those with indications for statin use, so it is difficult to view such analyses as informing on whether statins have an individual-level effect on dementia risk. Instead, they answer the question, “What impact does prescription of statins, under current rules and physician preferences, have on the incidence of dementia in our population?” These estimates reflect only specific prescribing pattern on dementia risk, and are strongly influenced by both the breadth and nature of indications for statin use. As the indications for statin use expand, it is not clear that the effect estimates from the currently available studies remain relevant to today’s prescribing patterns. New studies restricted to those with indications for statin use may allow better estimation of whether statins have an etiologic effect, but, in practice, even these studies are challenging. Under current clinical guidelines, persons with indications for statin use who are not taking statins are likely to have medical contraindications, limited access to preventative care, or other factors related to to access or motivation; these factors are difficult to account for analytically.


Results from Other Lines of Research

Clinical Trials

The relation between statin use and cognitive endpoints has been considered in several randomized clinical trials (RCTs). Smaller RCTs have been inconsistent, suggesting null (Kostis, Rosen, & Wilson, 1994), adverse (Muldoon et al., 2000; Muldoon, Ryan, Sereika, Flory, & Manuck, 2004), or protective (Carlsson et al., 2008) effects of statins on cognitive endpoints. These trials are also limited by follow-up of one year or less. However, two large, double-blind, placebo-controlled RCTs reported no effect of statins on cognition. After five years of follow-up, statin use was not associated with cognitive test performance in the Heart Protection Study, a randomized trial of statins in over 20,000 persons with high risk of vascular disease (Heart Protection Study Collaborative Group, 2002). Similarly, statin use was not associated with cognitive test performance or instrumental activities of daily living in the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) RCT, which randomized approximately 5800 persons to statins or placebo and followed them for three years (Shepherd et al., 2002; Trompet et al., 2010).

All-cause Dementia and Cognitive Decline

Results from prospective cohort studies of baseline statin use and cognitive change or dementia risk generally agree with the reviewed studies of baseline statin use and dementia. Work in the Religious Orders Study, the Three City Study, and the Cache County Study failed to suggest an association between baseline statin use and cognitive change or all-cause dementia (Ancelin et al., 2012; Arvanitakis et al., 2008; Zandi et al., 2005). However, results from the Indianapolis sample of the Ibadan-Indianapolis Dementia project suggest a protective association (Szwast et al., 2007). Strangely, the association reported in the Indianapolis cohort was driven by those who discontinued use during the three-year period, consistent with a “healthy user” bias (Szwast et al., 2007). Prospective studies embedded within electronic medical record databases (Smeeth, Douglas, Hall, Hubbard, & Evans, 2009; Wolozin et al., 2007) also suggest a protective association between statin use and dementia, but are limited by the relatively poor dementia classification available in such databases and lack of adjustment for education or other socioeconomic indicators.

Prospective cohort studies of all-cause dementia that consider statin use at or one year prior to the time of diagnosis concur with the reported literature on AD dementia using this approach, as they generally report protective associations (Bettermann et al., 2012; Beydoun et al., 2011; Cramer, Haan, Galea, Langa, & Kalbfleisch, 2008; Haag, Hofman, Koudstaal, Stricker, & Breteler, 2009; Li et al., 2010; Rea et al., 2005). However, as discussed above, such studies are particularly susceptible to bias due to reverse causation.


Discussion and Recommendations

Overall, the epidemiologic evidence does not support the hypothesis that statin use reduces the risk of AD or all-cause dementia. While research considering statin use at or within one year of the time of dementia consistently reports protective associations with AD dementia, such studies are particularly susceptible to reverse causation (given that persons with cognitive deterioration may be less likely to be prescribed or continue taking a statin). Conversely, consistent with the results of randomized clinical trials, studies of baseline statin use and risk of subsequent dementia individually and collectively report no association.

Given limitations of the current research, the relation between statin use and AD dementia in the general population remains an open question. As most of the existing studies were conducted prior to the recommendations for wider adoption of statin use for primary prevention of cardiovascular disease, research on the impact of statin use under current prescribing behavior will be useful. In addition, we know relatively little about the impact of statin use in midlife or sustained statin use from midlife to late life. Midlife measures of risk factors are often more strongly associated with Alzheimer’s disease or dementia risk than late life measures, and duration of risk factors may be a stronger predictor of cognitive status than measures at a single time point. While the biases discussed above pose a significant challenge for this type of research using observational data, clinical trials of sufficient duration are unlikely due to ethical and cost considerations.

Despite uncertainty about the relation between statin use and risk of Alzheimer’s disease or all-cause dementia, statins are considered relatively safe and have demonstrated benefits on cardiovascular disease and mortality. As such, the benefits of statins are sufficient to justify current treatment standards.


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