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Do Statins Reduce the Risk of Future Alzheimer-type Dementia?
Abstract & Commentary
By Michael Lin, MD, Assistant Professor of Neurology and Neuroscience, Weill Medical College of Cornell University. Dr. Lin reports no financial relationships relevant to this field of study.
Synopsis: Statin use, regardless of drug type, reduces the risk of dementia in later life.
Source: Haag MD, Hofman A, Koudstaal PJ, et al. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry 2009;80:13-17.
There is increasing evidence that risk factors for vascular disease also increase the risk for Alzheimer's disease (AD). In the largest prospective study to date specifically designed to examine statins and incidence of AD, the Rotterdam Study investigators report that statins are associated with reduced risk of AD, regardless of lipophilicity or apoE genotype.
Subjects were from a population-based cohort of 6,992 individuals found to be dementia-free at baseline, with virtually complete follow from initial enrollment (1990–1993) to January 2005. Regular assessments for incident dementia were made using validated instruments, and diagnoses of dementia subtypes were made using internationally accepted criteria. Drug exposures were determined using records from automated pharmacies in which 99.7% of subjects were registered, a key feature in eliminating recall bias. The primary analyses were for statin exposure (any or never) and for use of lipophilic or hydrophilic statins, presumed to differ in brain penetrance. Hazard ratios (HR) were calculated using Cox regression analysis, adjusting for several potential confounders. Compared to subjects who had never used a cholesterol-lowering agent, statin use was associated with decreased risk of AD (HR 0.57, 95% CI 0.37–0.90). HRs were equal for lipophilic (HR 0.54, 95% CI 0.32–0.89) and hydrophilic statins (HR 0.54, 95% CI 0.26–1.11), and protective effects were similar for subjects with an apoE4 allele (adjusted HR 0.50, 95% CI 0.26–0.94) and those without an apoE4 allele (adjusted HR 0.61, 95% CI 0.32–1.18).
As noted by the authors and the accompanying editorial, previous epidemiologic studies on cholesterol and risk reduction for AD have been somewhat mixed.1 Cross sectional/case-control studies initially suggested a protective effect of statins, but prospective studies were less consistent. In particular, the PROSPER study2 (5,804 subjects) and MRC/BHF Heart Protection Study3 (20,536 subjects) suggested no benefit for statins on cognition. However, despite the large sizes of these studies, incident dementia was not a primary endpoint in either, baseline cognitive status was unknown, and cognitive assessment consisted only of a mini-mental state examination or telephone interview at the last evaluation. In contrast, subjects in the Rotterdam Study were regularly evaluated using several validated instruments and DSM–III-R and NINCDS–ADRDA criteria for dementia and AD. Moreover, in the past year other large prospective studies specifically designed to examine statins and incident dementia or cognitive impairment have shown similar benefits.4,5
The use of statins in the treatment of AD appears to be a separate issue about which initial data are now becoming available. It appears that simvastatin6 and atorvastatin7 do not clearly alter disease course in mild/moderate AD, though there may be an effect when apoE subgroups are analyzed.
Subjects periodically ask whether statins may negatively impact cognition, based on anecdotal reports8 as well as some evidence in the medical literature.9 On the other hand, there is also evidence that use of statins may improve cognitive performance after six months.10
The Rotterdam study now adds to the accumulating weight of evidence that use of statins is associated with reduced risk for AD. Together with the known benefit of statins in reducing stroke risk, these data strongly favor aggressive use of statins whenever indicated for cholesterol reduction.
1. Sparks L. Statins and cognitive function. J Neurol Neurosurg Psychiatry 2009;80:1-2.
2. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet 2002;360:1623-1630.
3. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7-22.
4. Cramer C, Haan MN, Galea S, et al. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 2008;71: 344-350.
5. Sparks DL, Kryscio RJ, Sabbagh MN, et al. Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr Alzheimer Res 2008;5:416-421.
6. Sano M. Abstract T200: Multi-center, randomized, double-blind, placebo-controlled trial of simvastatin to slow the progression of Alzheimer's disease. Alzheimer's Association International Conference on Alzheimer's Disease, 2008.
7. Jones RW, Kivipelto M, Feldman H, et al. The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): Design and baseline characteristics. Alzheimers Dement 2008;4:145-153.
8. Beck M. Can a drug that helps hearts be harmful to the brain? The Wall Street Journal, Feb. 12, 2008.
9. Golomb BA, Dimsdale JE, White HL, et al. Abstract 1501: Do low dose statins affect cognition? Results of the UCSD statin study. Circulation 2006;114:II_289.
10. Parale GP, Baheti NN, Kulkarni PM, et al. Effects of atorvastatin on higher functions. Eur J Clin Pharmacol 2006;62:259-265.