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• W1505936134 abstract "In this issue, Li and colleauges report a beneficial effect of statins on the risk of Alzheimer's disease (AD) that is restricted to patients younger than 80 and unaffected by genetic, vascular, or demographic risk factors.1 Their conclusion is that earlier treatment with statins may be effective in lowering the risk of dementia. How should this finding be translated into clinical practice, if at all? Most dementias and AD are major late-life outcomes for which drug treatment options are limited in number and efficacy. The search is ongoing for agents that can slow progression or potentially prevent dementia. Statins are designed to lower low-density lipoprotein cholesterol (LDL-C) by blocking cholesterol synthesis in the liver. As a group, they are thought to prevent cardiovascular diseases by improving endothelial function, reducing inflammatory responses, maintaining stability of atherosclerotic plaques, and preventing the formation of thrombi.2 Even in those with normal cholesterol, statins might prevent vascular disease by reducing inflammation.3 The apparently pleiotropic benefits of statins have led to interest in using them to treat noncardiovascular conditions, some of which may exceed their intended reach. A recent analysis of The Health Improvement Network (THIN) data4 suggested that statins' primary benefits are for vascular outcomes and, perhaps, for dementia and AD and not for cancer or other non-cardiovascular outcomes, but the likelihood that vascular and metabolic risk factors such as hypertension, atherosclerosis, and type 2 diabetes mellitus have an important role in the development of dementia and AD is increasingly accepted, although still controversial. A fairly consistent observational literature exists that links higher cholesterol to higher risk of AD5,6 and cognitive decline. The ɛ4 allele of apolipoprotein E (APOE), a genotype that increases AD risk, is known to increase LDL-C and frequently modifies the effects of vascular factors on AD and other cognitive outcomes.7 It seems logically to follow that lowering LDL-C could lower the risk of AD. Evidence also exists that statins may reduce blood pressure and stroke risk.8 Given the strong links between hypertension and stroke and AD, it is reasonable to hope for an effect of statin treatment on AD risk. In previous work, Li9 has reported in autopsy studies that statin users exhibited less AD pathology than nonusers. These various mechanisms give scientists and medical care providers reason to hope that statins may prevent neurodegeneration and protect against progression for those with dementia and of AD. In addition to the results that Li presents in the article in this issue, four well-done, population-based observational studies agree closely with Li's results and show a protective effect of statin therapy on the risk of AD and dementia,10–13 even after adjustment for demographic and vascular confounders. The results from these five studies are fairly consistent, ranging from a 38% to 43% lower risk of AD or dementia with an average follow up time of 5 to 6 years. At the same time, several controlled randomized trials of statin therapy have reported no benefits for progression in AD from treatment.14,15 Two older trials,16,17 using pravastatin and simvastatin, respectively, in patients with substantial heart disease found no effect of statin treatment on cognitive outcomes. Part of the explanation for the dramatic differences between observational studies and clinical trials may be that treatment trials tend to be short term and include patients with advanced disease who are typically older. Observational cohort studies such as Li's, normally include a wider age range of people with normal cognition to more-advanced disease and are usually longer in duration. Li and colleagues report greater benefits from statin therapy for those younger than 80, as did a previous study.18 Consistent with these findings, in one of the smaller trials6 of atorvastatin, the authors noted that an earlier stage of progression, higher starting cholesterol, and APOE ɛ4 status could modify the effects of statin on change in cognitive function in patients with AD. More benefit at younger ages argues for earlier intervention. It has been a given for decades in the cardiovascular disease prevention arena that early risk reduction is the key to prevention. This notion led to behavioral modification programs targeting risk factors such as exercise, hypertension, and smoking. By comparison, research in AD has recently to placed greater emphasis on prevention, and AD intervention programs have begun to target mid-life risk factors for AD such as exercise and weight control. Recent evidence suggests that midlife obesity increases risk of late-life dementia, whereas obesity in old age may be protective.19,20 Similar reports exist for lipids and blood pressure or hypertension in relation to AD and dementia. Vascular and metabolic factors at mid-life may decrease late-life cognitive performance. Several reports have linked white matter and regional brain atrophy to midlife obesity and blood pressure. Do the Li results mean that treatment will be more effective at younger ages? The greater difficulty of reversing or slowing down more-advanced pathology may attenuate the effectiveness of interventions and treatments targeted at older people to prevent cognitive impairments and dementias. Selective survival and competing risk from comorbidities and death also interfere with treatment efficacy. Despite Li's interesting findings, there is mixed evidence and some controversy regarding the efficacy of statin treatment for cardiovascular risk in patients aged 80 and older. Some data on age-specific treatment patterns suggest that older patients may receive less treatment and less-aggressive treatment, albeit perhaps for solid medical reasons, although one study concluded that “chronological age … should not exclude patients from receiving [statin] therapy.”21 There has been no primary prevention trial of statins for AD as yet and may never be. As Li notes, “a primary prevention trial faces great challenges because of the current lack of tools to assess disease-modifying effects in the absence of clinical signs of dementia and requires the recruitment and retention of a large cohort of subjects over a prolonged follow-up period.”1 Maximizing the potential benefit of early versus later treatment requires sensitive and specific screening methodologies that can identify who is at risk of developing dementia. Otherwise, patients are treated unnecessarily and exposed to whatever side effects a treatment may have, and somebody must pay for treatment. It is also unclear which, if any, of the many statins offer the greatest benefits for AD prevention, so treatment decisions are not clear cut. The cohort studied in Li's work is fairly typical of older patient populations in the United States. Analysis of national data on patterns of statin use over time suggest a doubling in treatment prevalence during the period of the study (National Health and Nutrition Examination Studies 1999/2000 through 2004) in patients aged 60 and older. In 2006, according to the National Center for Health Statistics, antihyperlipidemic agents were prescribed more than 100 million times in the United States, of which 53% were atorvastatin or simvastatin. Whether older patients with cardiovascular risk are less likely to be treated with statins or to be treated with lower doses or are less adherent is not clear, but it seems likely. As Li and colleagues note, “another potential bias may be due to older participants having different indications for statin therapy and receiving a combination of slightly lower dosages with shorter durations of exposure than younger participants.”1 Overall, patients aged 80 and older took statins less often and for slightly less time than those younger than 80. That this translates to less benefit does not automatically follow; some evidence taken from people aged 75 and older suggests that total cholesterol is less predictive of cardiovascular problems than in younger people and that older adults may experience more adverse reactions from statins. At the same time, adherence may decrease in elderly patients because of side effects. There have been insufficient numbers of people aged 80 and older in randomized trials to establish the benefit, efficacy, and risk of taking statins in this age group, regardless of which outcome is of concern. Li and colleagues have revealed a “natural history” of statin use and cognitive decline in an older population that is hopeful but leaves many unanswered questions for clinicians and scientists. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the author and has determined that the author has no financial or any other kind of personal conflicts with this paper. The National Institute on Aging provided all funding for this effort under RO1 AG12975. Author Contributions: Dr. Mary Haan was solely responsible for the writing, research, and final version of this editorial. Sponsor's Role: NIA did not influence any of the design, methods, subject recruitment, data collections, analysis, or preparation of editorial." @default.
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• W1505936134 date "2010-07-01" @default.
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• W1505936134 title "Can Statins Prevent Dementia in Older Adults?" @default.
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