Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease

Wolozin, Benjamin; Wang, Stanley W.; Li, Nien Chen; Lee, Austin; Lee, Todd A.; Kazis, Lewis E.

doi:10.1186/1741-7015-5-20

Cited by 346 publications

(290 citation statements)

References 42 publications

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“…Our study suggests that statins have minimal or no effect on these eye diseases. We found no evidence to support a reported protective effect against Parkinson's disease [35], multiple sclerosis [36], rheumatoid arthritis [37,38], psoriasis [39] or effects on systemic lupus erythematosus [39,40]. Concern that statins are associated with an increased risk of upper motor neuron lesions was raised based on spontaneous reports to the World Health Organization Programme for International Drug Monitoring [13].…”

Section: Comparison Of Results With Previous Studiesmentioning

confidence: 72%

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Smeeth

Douglas

Hall

et al. 2008

Brit J Clinical Pharma

210

201

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The effect of statins on cardiovascular outcomes is well established.• Effects on numerous other health outcomes have been claimed, but results have been inconsistent.• Previous observational studies may have been affected by selection bias and confounding. WHAT THIS STUDY ADDS• This study was larger and more statistically powerful than the combined total of data from all randomized trials of statins undertaken to date.• The validity of the study is supported by findings for vascular outcomes being comparable to those observed in large randomized controlled trials.• There was little evidence to support effects of statins beyond their established effects on cardiovascular disease. AIMSTo assess the effect of statins on a range of health outcomes. METHODSWe undertook a population-based cohort study to assess the effect of statins on a range of health outcomes using a propensity score-based method to control for differences between people prescribed and not prescribed statins. We validated our design by comparing our results for vascular outcomes with the effects established in large randomized trials. The study was based on the United Kingdom Health Improvement Network database that includes the computerized medical records of over four and a half million patients. RESULTSPeople who initiated treatment with a statin (n = 129 288) were compared with a matched sample of 600 241 people who did not initiate treatment, with a median follow-up period of 4.4 years. Statin use was not associated with an effect on a wide range of outcomes, including infections, fractures, venous thromboembolism, gastrointestinal haemorrhage, or on specific eye, neurological or autoimmune diseases. A protective effect against dementia was observed (hazard ratio 0.80, 99% confidence interval 0.68, 0.95). There was no effect on the risk of cancer even after Ն8 years of follow-up. The effect sizes for statins on vascular end-points and mortality were comparable to those observed in large randomized trials, suggesting bias and confounding had been well controlled for. CONCLUSIONSWe found little evidence to support wide-ranging effects of statins on health outcomes beyond their established beneficial effect on vascular disease.

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Section: Comparison Of Results With Previous Studiesmentioning

confidence: 72%

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Smeeth

Douglas

Hall

et al. 2008

Brit J Clinical Pharma

210

201

View full text Add to dashboard Cite

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“…Taken together, outcomes from randomized clinical trials do not confirm the findings from observational studies that statins might reduce the risk of dementia or decelerate cognitive decline [18]. Strong evidence indicates that cardiovascular disease and some of its risk factors are important determinants for the development of dementia.…”

Section: Discussionmentioning

confidence: 77%

“…Cross-sectional and case-control studies have generally indicated a beneficial effect of statins on cognitive outcomes [5,12,18], while observational studies with long follow-up periods have failed to confirm these results [17,19]. This discrepancy might be explained by prescription bias, in that subjects who are cognitively impaired are less likely to have been prescribed a statin.…”

Section: Introductionmentioning

confidence: 99%

Pravastatin and cognitive function in the elderly. Results of the PROSPER study

et al. 2009

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Observational studies have given conflicting results about the effect of statins in preventing dementia and cognitive decline. Moreover, observational studies are subject to prescription bias, making it hard to draw definite conclusions from them. Randomized controlled trials are therefore the preferred study design to investigate the association between statins and cognition. Here we present detailed cognitive outcomes from the randomized placebocontrolled PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cognitive function was assessed repeatedly in all 5,804 PROSPER participants at six different time points during the study using four neuropsychological performance tests. After a mean follow-up period of 42 months, no difference in cognitive decline at any of the cognitive domains was found in subjects treated with pravastatin compared to placebo (all p [ 0.05). Pravastatin treatment in old age did not affect cognitive decline during a 3 year follow-up period. Employing statin therapy in the elderly in an attempt to prevent cognitive decline therefore seems to be futile.

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“…Currently there is considerable confusion about the relationship between cholesterol and synucleinopathies (30)(31)(32). Although some studies suggest that cholesterol-lowering drugs have a protective role, others point to associations between low cholesterol and increased risk of PD.…”

Section: Discussionmentioning

confidence: 99%

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Valastyan¹,

Termine²,

Lindquist³

2014

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are neurodegenerative diseases associated with toxicity of the lipid-binding protein α-synuclein (α-syn). When expressed in yeast, α-syn associates with membranes at the endoplasmic reticulum and traffics with vesicles out to the plasma membrane. At higher levels it elicits a number of phenotypes, including blocking vesicle trafficking. The expression of α-syn splice isoforms varies with disease, but how these isoforms affect protein function is unknown. We investigated two of the most abundant isoforms, resulting in deletion of exon four (α-synΔ4) or exon six (α-synΔ6). α-SynΔ4, missing part of the lipid-binding domain, had reduced toxicity and membrane binding. α-SynΔ6, missing part of the protein-protein interaction domain, had reduced toxicity but no reduction in membrane binding. To compare the mechanism by which the splice isoforms exert toxicity, equally toxic strains were probed with genetic modifiers of α-syn-induced toxicity. Most modifiers equally altered the toxicity induced by the splice isoforms and full-length α-syn (α-synFL). However, the splice isoform strains responded differently to a sterol-binding protein, leading us to examine the effect of sterols on α-syn-induced toxicity. Upon inhibition of sterol synthesis, α-synFL and α-synΔ6, but not α-synΔ4, showed decreased plasma membrane association, increased vesicular association, and increased cellular toxicity. Thus, higher membrane sterol concentrations favor plasma membrane binding of α-synFL and α-synΔ6 and may be protective of synucleinopathy progression. Given the common use of cholesterol-reducing statins and these potential effects on membrane binding proteins, further investigation of how sterol concentration and α-syn splice isoforms affect vesicular trafficking in synucleinopathies is warranted.

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Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease

Cited by 346 publications

References 42 publications

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Pravastatin and cognitive function in the elderly. Results of the PROSPER study

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

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