We found statin use to be associated with a significant reduction in the incidence of dementia/CIND among a representative sample of community-dwelling Mexican Americans which was unaffected by confounding for key covariates. Compared to our study, the results of other epidemiologic studies evaluating the effect of statins on dementia have been variable,13–20
with frequent debate regarding methodologic issues in these studies, including the presence of indication bias in early case-control studies.12
It is striking to note, however, that risk reductions were seen in all epidemiologic studies, with the exception of one study.19
However, the reductions were not significant in the main analyses of most of the cohort studies.16,18–20
Two major clinical trials are often cited as providing evidence that statins do not have an effect on the incidence of dementia: the Prospective Study of Pravastatin in the Elderly (PROSPER)5
and the Medical Research Council/British Heart Foundation Heart Protection Study27
; however, because of methodologic limitations in relation to dementia outcomes in these two trials, the results of these trials are difficult to evaluate. Dementia incidence or cognitive outcomes were not preplanned endpoints in either of them, neither study included a clinical cognitive evaluation, and numbers of patients with follow-up information for cognitive evaluations were not reported in either study manuscript. In PROSPER a post hoc analysis compared changes in cognitive scores over a 3-year period between statin-treated and placebo patients and found no significant differences. In the MRC/BHF HPS trial,27
similar percentages of participants (0.3% in each—statin vs placebo—group) developed dementia during the 5-year follow-up period. The report did not state how the outcome of dementia was determined (e.g., reported as an adverse event or by follow-up phone interview).
Four cohort studies also examined the relationship between lipid lowering therapy (LLT) use and risk of dementia.16,18–20
All of these studies had differing study designs, and only one study evaluated statin use as a time-dependent covariate.18
In the three studies using a single timepoint to ascertain statin use, the percentages of participants on statins were low (ranging from 4% to 12%).16,19–20
In the study with design similar to the SALSA study,18
similarities include the length of follow-up time (5 years) and the method of analysis (Cox proportional hazards models with statin use as a time-dependent covariate in the model). Some of the differences in this study include the outcome variable (dementia vs CIND and dementia), a lower percentage of statin use (17%), less frequent ascertainment of statin use (every 2 years), use of a pharmacy database compared to visual inspection, a population that was mostly white (91%), and an average age at study entry that was older (75 years of age compared to 70 years of age in SALSA). Of note, this study found that statin use may provide some benefit for younger individuals (evaluation of effect of statin use on dementia after stratification by age [<80 and ≥ 80 years] and with one APOE
4 allele: HR = 0.33, 95% CI = 0.10, 1.04). 16,18
Comparison of clinical trials to observational studies are made difficult by the kinds of participants that can be included in each.
The effects of statin use on the incidence of dementia/CIND seen in this analysis may be due in part to some of the methodologic strengths in this study. Important strengths include the prospective collection of data, including medication data ascertained by semiannual phone updates and annual visual inspection of medications (allowing for use of a time-dependent statin covariate in the model with evaluations at five timepoints including baseline), and clinical evaluation with adjudication of dementia cases used for diagnosis of dementia and CIND. There was a large proportion of participants with diabetes in this population with high risk of cardiovascular disease, and therefore these participants had greater overall statin use (27%) compared to most of the previously reported cohort studies. In SALSA, the annual follow-up visits were conducted from 2000 to 2006, during which time there was a significant increase in statin use in the general population as well as an increase in statin use among the elderly, especially following the issuance of 2001 Adult Treatment Panel (ATP) III guidelines.28
During this period, adherence to statin therapy was also reported to be improved for patients with high cardiovascular risk or with previous stroke, albeit still somewhat poor (<60% 6 months after initiation).28
The data from our study reflect these trends including an increase in statin use (9% at baseline increasing to 26% at visit 4; see ) and adherence to therapy (58% used statins two or more follow-up periods of the study).
Although we combined dementia and CIND to improve statistical power, longitudinal studies have shown that individuals diagnosed with MCI have a much higher risk than cognitively normal people of progressing to dementia or AD.24
One of the potential limitations of this study is the lack of power to evaluate the effects of statins on specific dementia etiologies. In addition, while the non mortality loss to follow-up was generally low in this study (<17% overall), there was less loss to follow-up in statin users (7%) compared to nonusers (18%). In the nonusers group, participants lost to follow-up and those remaining in the study were similar with respect to gender, age, and history of heart failure, diabetes, stroke, myocardial infarction, and high blood pressure at baseline. Statin users had higher baseline prevalence of type 2 diabetes, myocardial infarction, and high blood pressure. There was no difference by use group for baseline heart failure or stroke. Although there are some differences in health status, we adjusted for these factors in analysis. The difference in mortality attrition by user group is slight. Statin users were only slightly less likely to die (14%) compared to the nonusers group (17%). Statin use was not associated with survival in a Cox regression model even when adjusted for covariates (HR: 0.92; 95% CI: 0.69–1.20) among participants not lost to follow-up. Nevertheless, indication bias, differential loss to follow-up, and competing risk could bias the estimate of effect for statin use away from the null.
To date, there are no primary prevention trials of statins for any kind of dementia or cognitive decline in normal people. An ongoing trial of statins as potential treatment for delaying progression of AD29
has not so far provided clear evidence of benefit. Additional questions and future research suggested in particular by this analysis involve the investigation of differences of statin use and association of dementia and CIND in individuals with stroke and diabetes, and the impact of statins on CIND and subtypes of dementia.