Use of Lipid-Lowering Agents, Indication Bias, and the Risk of Dementia in Community-Dwelling Elderly People

Rockwood, Kenneth; Kirkland, Susan; Hogan, David B.; MacKnight, Chris; Merry, Heather; Verreault, René; Wolfson, Christina; McDowell, Ian

doi:10.1001/archneur.59.2.223

Cited by 480 publications

(302 citation statements)

References 27 publications

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“…Efforts to address the broader issue of whether statins affect AD have yielded ambiguous results. Epidemiologic studies point to an association between chronic statin treatment and low risk of AD (15,62), but a recent review concluded that, although experimental studies support a link between cholesterol and amyloid-␤ peptide production, available prospective studies show no benefits for any statin tested (63). The more specific question of whether activated microglia make positive or negative contributions to disease progression is also unresolved.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Baudry

Liu

et al. 2004

Journal of Biological Chemistry

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Inflammatory responses involving microglia, the resident macrophages of the brain, are thought to contribute importantly to the progression of Alzheimer's disease (AD) and possibly other neurodegenerative disorders. The present study tested whether the mevalonate-isoprenoid biosynthesis pathway, which affects inflammation in many types of tissues, tonically regulates microglial activation. This question takes on added significance given the potential use of statins, drugs that block the rate-limiting step (3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)) in mevalonate and cholesterol synthesis, in AD treatment. Both mevastatin and simvastatin caused a concentration-and time-dependent activation of microglia in cultured rat hippocampal slices. This response consisted of a transformation of the cells from a typical resting configuration to an amoeboid, macrophage-like morphology, increased expression of a macrophage antigen, and up-regulation of the cytokine tumor necrosis factor-␣. Evidence for proliferation was also obtained. Statin-induced microglial changes were blocked by mevalonate but not by cholesterol, indicating that they were probably due to suppression of isoprenoid synthesis. In accord with this, the statin effects were absent in slices co-incubated with geranylgeranyl pyrophosphate, a mevalonate product that provides for the prenylation of Rho GTPases. Finally, PD98089, a compound that blocks activation of extracellularly regulated kinases1/2, suppressed statin-induced up-regulation of tumor necrosis factor-␣ but had little effect on microglial transformation. These results suggest that 1) the mevalonate-isoprenoid pathway is involved in regulating microglial morphology and in controlling expression of certain cytokines and 2) statins have the potential for enhancing a component of AD with uncertain relationships to other features of the disease.High levels of cholesterol, and in particular of cholesterol esters (1), influence the generation and aggregation of ␤-amyloid peptides in dissociated cell cultures (2-6) and transgenic mice (7). Patients with high plasma cholesterol levels and cardiovascular diseases have increased risk of Alzheimer's disease (AD) 1 (8 -10), and there is evidence that statins, a family of compounds that inhibit the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase: HMG-CoA reductase), decrease the incidence of the disease (11, 12). These observations have led to an extensive and ongoing evaluation of statins as preventive treatments for Alzheimer's disease (13-16).Mevalonate, a cholesterol precursor, the synthesis of which is blocked by statins, is converted into several bioactive compounds. Among these, the isoprenoids are of particular importance because, among other functions, they provide for the covalent addition of lipid moieties (prenylation) to regulatory proteins (17) and thereby affect critical cell functions. Prenylation by the mevalonate products farnesyl diphosphate and geranylgeranyl diphosphate, ...

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Section: Discussionmentioning

confidence: 99%

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Baudry

Liu

et al. 2004

Journal of Biological Chemistry

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“…For example, the e4 allele of the Apolipoprotein E gene (APOE) has emerged as a clear genetic susceptibility factor for Alzheimer's dementia [8], although it has not resulted in effective therapeutic strategies, thus far. Numerous observational studies have reported putative protective effects in relation to dietary intake and nutritional supplementation (fish oils [9], folate [10] and vitamins E and C [11]); mental [12] and physical exercise [13]; and medications including estrogen therapy [14], non-steroidal anti-inflammatory drugs [15], and statins [16]. Unfortunately, the limited randomized clinical trials to date have not supported a role for these agents in the prevention of AD [17,18], but more studies need to be done.…”

Section: Risk and Preventive Factors And The Public Health Impact Of mentioning

confidence: 99%

Alzheimers and Dementia in the Oldest-Old: A Century of Challenges

Kawas

Corrada²

2006

CAR

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Alzheimer's disease (AD) is the most common type of dementia in the US and much of the world with rates increasing exponentially from age 65. Increases in life expectancy in the last century have resulted in a large number of people living to old ages and will result in a quadrupling of AD cases by the middle of the century. Preventing or delaying the onset of AD could have a huge impact in the number of cases expected to develop. The oldest-old are the fastest growing segment of the population and are estimated to account for 12% of the population over 65. Establishing accurate estimates of dementia and AD rates in this group is crucial for public health planning. Prevalence and incidence estimates above age 85 are imprecise and inconsistent because of the lack of very old individuals in most studies. Moreover, risk and protective factors in our oldest citizens have been studied little, and clinical-pathological correlations appear to be poor. We introduce The 90+ Study, established to address some of the unanswered questions about AD and dementia in the oldest-old. Our preliminary results show that close to half of demented oldest-old do not have known cerebral pathology to account for their cognitive deficits. Furthermore, the APOE-e4 allele appears to be a risk factor for AD only in the women in our study. In addition to the challenge of preventing and treating AD, the oldest-old will require major investigative energy to better understand the concomitants of longevity, the causes of dementia, and the factors that promote successful aging in oldest citizens.

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“…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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Use of Lipid-Lowering Agents, Indication Bias, and the Risk of Dementia in Community-Dwelling Elderly People

Cited by 480 publications

References 27 publications

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Alzheimers and Dementia in the Oldest-Old: A Century of Challenges

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

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