Integrating health into cognitive aging: toward a preventive cognitive neuroscience of aging.
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. 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 (LDLC) 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. Even in those with normal cholesterol, statins might prevent vascular disease by reducing inflammation. 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) data 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 AD and cognitive decline. The e4 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. 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. 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, Li 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, 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. Two older trials, 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. Consistent with these findings, in one of the smaller trials of atorvastatin, the authors noted that an earlier stage of progression, higher starting cholesterol, and APOE e4 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. 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 DOI: 10.1111/j.1532-5415.2010.02907.x