Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26‐week randomized, placebo‐controlled, double‐blind trial

Simons, Mikael; Schwärzler, Frank; Lütjohann, Dieter; Bergmann, Klaus von; Beyreuther, Konrad; Dichgans, J.; Wormstall, H.; Hartmann, Tobias; Schulz, Jörg B.

doi:10.1002/ana.10292

Cited by 389 publications

(278 citation statements)

References 18 publications

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“…Sjogren et al (2003) observed reduced CSF ␣-and ␤-sAPP levels after 12 weeks of simvastatin therapy. Moreover, statin use has been correlated with a reduction in serum and CSF A␤ levels and brain hydroxycholesterol levels (Buxbaum et al, 2002;Simons et al, 2002). It has been argued that the basis of these effects is the dependence of APP processing on neuronal membrane cholesterol content.…”

Section: Discussionmentioning

confidence: 99%

“…Statin treatment has been shown to reduce A␤ production both in vitro and in animal models (Fassbender et al, 2001;Petanceska et al, 2002;Parvathy et al, 2004). Recent prospective studies indicate that statin use reduces soluble A␤ levels in the brain and may improve cognitive function (Buxbaum et al, 2002;Simons et al, 2002;Sjogren et al, 2003;Caballero and Nahata, 2004). These effects are thought to result from reduction in amyloidgenic amyloid precursor protein (APP) processing owing to the sensitivity of ␤ and ␥ secretases to neuronal membrane cholesterol content (Simons et al, 1998;Kojro et al, 2001;Burns and Duff, 2002;Wahrle et al, 2002;Wolozin, 2002;Cordy et al, 2003;Puglielli et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

Cordle¹,

Landreth²

2005

J. Neurosci.

161

109

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Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar ␤-amyloid (A␤) in the brain, a fulminant microglialmediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the A␤-stimulated expression of interleukin-1␤ and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal A␤ production and microglia-directed inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

Cordle¹,

Landreth²

2005

J. Neurosci.

161

109

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“…[12][13][14][15] All had placebo rather than standard care comparators. RCTs (reported in 23 publications [13][14][15][36][37][38][39][40][41][42][43][44][45][46][47][48][50][51][52]55,56,62,64 ) enrolled subjects with normal cognition at baseline, four RCTs (reported in seven publications 12,54,[57][58][59][60][61] ) enrolled patients with AD, and three RCTs enrolled other cognitively impaired subjects (traumatic brain injury, 53,63 and neurofibromatosis type 1 49 ). Simvastatin (eight trials), pravastatin (eight trials), and lovastatin (six trials) were most frequently utilized in the statin RCTs.…”

Section: Assessment Of Heterogeneity and Meta-regression Analysesmentioning

confidence: 99%

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

et al. 2015

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BACKGROUND:In 2012, the United States Food and Drug Administration (FDA) issued a warning regarding potential adverse effects of HMG-CoA reductase inhibitors (statins) on cognition, based on the Adverse Events Reporting System and a review of the medical literature. We aimed to synthesize randomized clinical trial (RCTs) evidence on the association between statin therapy and cognitive outcomes. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL through December 2012, and reviewed published systematic reviews of statin treatment. We sought RCTs that compared statin treatment versus placebo or standard care, and reported at least one cognitive outcome (frequency of adverse cognitive events or measurements using standard neuropsychological cognitive test scores). Studies reporting sufficient information to calculate effect sizes were included in metaanalyses. Standardized and unstandardized mean differences were calculated for continuous outcomes for global cognition and for pre-specified cognitive domains. The main outcome was change in cognition measured by neuropsychological tests; an outcome of secondary interest was the frequency of adverse cognitive events observed during follow-up. RESULTS: We identified 25 RCTs (all placebo-controlled) reporting cognitive outcomes in 46,836 subjects, of which 23 RCTs reported cognitive test results in 29,012 participants. Adverse cognitive outcomes attributable to statins were rarely reported in trials involving cognitively normal or impaired subjects. Furthermore, meta-analysis of cognitive test data (14 studies; 27,643 participants) failed to show significant adverse effects of statins on all tests of cognition in either cognitively normal subjects (standardized mean difference 0.01, 95 % confidence interval, CI, −0.01 to 0.03, p=0.42) or Alzheimer's disease subjects (standardized mean difference −0.05, 95 % CI −0.19 to 0.10, p=0.38). CONCLUSIONS: Statin therapy was not associated with cognitive impairment in RCTs. These results raise questions regarding the continued merit of the FDA warning about potential adverse effects of statins on cognition.

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“…In addition to the cholesterol lowering effect, statins have many pleiotropic effects, such as reducing Aβ production, suppressing inflammatory responses, protecting neurons from excitotoxins, apoptosis, and oxidative stresses, and promoting synaptogenesis [16][17][18][19] . In particular, statins have been linked to the reduced prevalence of AD in statin-prescribed populations [20,21] , the improved cognition in normo-cholesterolemic patients [22] , and the slowed cognitive decline in mild-to-moderate AD patients [23] . It has been shown that simvastatin was effective in reversing learning and memory deficits in an aged AD mouse model [24] .…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

et al. 2014

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Aim: To investigate whether atorvastatin treatment could prevent Aβ 1-42 oligomer (AβO)-induced synaptotoxicity and memory dysfunction in rats, and to elucidate the mechanisms involved in the neuroprotective actions of atorvastatin. Methods: SD rats were injected with AβOs (5 nmol, icv). The rats were administrated with atorvastatin (10 mg·kg -1 ·d -1 , po) for 2 consecutive weeks (the first dose was given 5 d before AβOs injection). The memory impairments were evaluated with Morris water maze task. The expression of inflammatory cytokines in the hippocampus was determined using ELISA assays. The levels of PSD-95 and p38MAPK proteins in rat hippocampus were evaluated using Western blot analysis. For in vitro experiments, cultured rat hippocampal neurons were treated with AβOs (50 nmol/L) for 48 h. The expression of MAP-2 and synaptophysin in the neurons was detected with immunofluorescence. Results: The AβO-treated rats displayed severe memory impairments in Morris water maze tests, and markedly reduced levels of synaptic proteins synaptophysin and PSD-95, increased levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and p38MAPK activation in the hippocampus. All these effects were prevented or substantially attenuated by atorvastatin administration. Pretreatment of cultured hippocampal neurons with atorvastatin (1 and 5 µmol/L) concentration-dependently attenuated the AβO-induced synaptotoxicity, including the loss of dendritic marker MAP-2, and synaptic proteins synaptophysin and PSD-95. Pretreatment of the cultured hippocampal neurons with the p38MAPK inhibitor SB203580 (5 µmol/L) blocked the AβO-induced loss of synaptophysin and PSD-95. Conclusion: Atorvastatin prevents AβO-induced synaptotoxicity and memory dysfunction through a p38MAPK-dependent pathway.

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Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26‐week randomized, placebo‐controlled, double‐blind trial

Cited by 389 publications

References 18 publications

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

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