Statins Do Not Appear to Slow the Progression of Alzheimer's Disease
Statins Do Not Appear to Slow the Progression of Alzheimer's Disease
Abstract & Commentary
By Michael Lin, MD. Dr. Lin is Assistant Professor of Neurology at Weill Cornell Medical College. Dr. Lin reports no financial relationships relevant to this field of study.
Synopsis: In this large, well-powered, prospective, randomized trial, treatment of Alzheimer's patients with a high-dose statin did not have a significant effect on cognitive decline.
Source: Feldman HH, et al., on behalf of the LEADe Investigators. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010;74;956-964.
In the recently published lead study (Lipitor's effect in Alzheimer's Dementia), Feldman and colleagues examined the safety and efficacy of atorvastatin in patients with mild to moderate Alzheimer's disease (AD). This was an international, multicenter, double-blind, randomized, placebo-controlled trial in which 640 subjects with AD (age 50-90, MMSE 13-25, LDL 95-195 mg/dL, no significant cardiac or cerebrovascular disease) were randomized to atorvastatin (80 mg/day) or placebo for 18 months, followed by a two-month washout period.
Treatment with atorvastatin produced a 72 mg/dL drop in LDL, compared to a 1 mg/dL drop in the placebo group. However, there was no significant difference compared to placebo in either cognition or global function as primary endpoints, measured by the AD Assessment Scale-Cognitive subportion and the AD Cooperative Study Clinical Global Impression of Change. A volumetric MRI substudy in 10% of subjects showed a significant smaller annualized decrease in hippocampal volume with atorvastatin, but the MRI subsample was not representative of the whole study; there were significant differences in baseline demographics between treatment arms, and a significant effect on ADCS-CGIC favoring atorvastatin, neither of which was present in the entire study. Treatment with atorvastatin was safe. Of note, there were no adverse cognitive effects, despite anecdotal reports of cognitive impairment with statins. In fact, at every time point after baseline, the ADAS-Cog score was slightly (but not significantly) better in the atorvastatin group.
This study provides class II evidence that intensive lipid lowering therapy in mild to moderate AD does not benefit either cognition or global function. It is the largest and longest randomized, double-blind, placebo-controlled trial of statins in AD to date. The sample size afforded at least 80% power to detect a 30% to 40% effect in either primary endpoint at 18 months with a two-tailed test, assuming dropout of up to 30%. All the assumptions made in study design were met, including the rate of cognitive decline in the placebo group, the dropout rate, and the degree of cholesterol lowering.
On the other hand, one limitation of the study is that subjects were excluded if there was a definite indication for use of a statin, or any significant cardiovascular or cerebrovascular disease. It is possible that AD subjects with higher LDL levels or more significant vascular disease may have shown a greater degree of benefit.
Commentary
This study continues the saga concerning the role of statins in AD prevention or therapy. In cultured cells and transgenic mice, cholesterol modulates Aβ production, and statins reduce Aβ production. In retrospective case-control studies, statins are associated with reduced risk of AD. However, prospective epidemiologic studies have been mixed, and two large randomized cardiovascular prevention trials with cognition as secondary endpoints have not shown any benefit. Another large clinical trial of a statin in AD (simvastatin) was reported to be negative at an international meeting, but formal publication is pending.
Based on this study, use of statins solely as treatment for AD is not indicated. Their effects on AD, when given for vascular or lipid-lowering indications, remain to be seen, and their role in prevention is still unclear.
In this large, well-powered, prospective, randomized trial, treatment of Alzheimer's patients with a high-dose statin did not have a significant effect on cognitive decline.Subscribe Now for Access
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