Commentary on “The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): Design and baseline characteristics”

Jones et al present in this journal edition the design and baseline characteristics of the LEADe study for the LEADe study group1. The LEADe study is an international, mult-center, randomized, double-blind, placebo controlled study in conjunction with donepezil as a treatment for Alzheimer's disease. The rationale of this clinical trial stems from the growing belief that lipid lowering drugs including statins could lessen the risk of dementia and perhaps alter the rate of progression of Alzheimer's disease. Several epidemiological studies have suggested the protective roles of statins2–6, but a number of cohort studies have not found a clear association between statins and reduced risk of dementia7–9. There are plausible biological reasons why it is appropriate to test lipid-lowering drugs including statins as treatments for Alzheimer's disease. Statins have been shown to have some influence on the pathogenesis of Alzheimer's disease. They have also been shown to have anti-inflammatory, anti-oxidant, and neuro-protective properties10. Collectively these observations provide the impetus to pursue randomized clinical trials of atorvastatin and other statins as treatments for Alzheimer's disease. From the baseline LEADe data, several observations should be identified. First, the total cholesterol is recorded to be slightly elevated at 224 mg/dl. The LDL was reported to be elevated at 143 mg/dl and the HDL was reported to be normal at 64mg/dl. The triglycerides were slightly elevated as well. Previously, we have reported a similar pattern in a smaller cohort of individuals11 that is not influenced by apolipoprotein E genotype12. Given this observation has been now reproduced in the large multi-center LEADe clinical trial, this pattern of mildly-elevated total cholesterol, LDL and triglycerides represents the lipid profile of Alzheimer's disease and heretofore should be referred to as such.. Part of the impetus for pursuing a multi-center clinical trial comes from the findings of the Alzheimer's Disease Cholesterol-Lowering Treatment Trial (ADCLT), a single-center, double-blind, placebo-controlled trial investigating the effect of atorvastatin as a treatment of Alzheimer's disease13. The ADCLT was a positive pilot study indicating that atorvastatin provided benefit on the course of mild to moderate Alzheimer's disease in subjects receiving background therapy of cholinesterase inhibitor. This study did show some trends toward cognitive benefit on the ADAS-Cog in the treated group compared to the placebo group. The trends in that pilot study were tantalizing and beg to identify the mechanism of action for the observed effect. Secondary analyses of the ADCLT have been performed to explore this. In the ADCLT, the group treated with 80mg of atorvastatin had significant reductions in total cholesterol. Additionally LDL and VLDL were reduced as well. However, there are no effects SOD or GPX14. Additionally there was no reduction in Aβ40 or 42 and no effects of cerulpolasmin in that study15. The preliminary data suggests that the mechanism of action was not driven by effects other than the reduction of cholesterol. The secondary analysis of the ADCLT also reveals that the effect of atorvastatin was not seen in all groups of individuals. Specifically, subjects with higher cholesterols (greater than 200 mg/dl) had significantly positive effects on ADAS-Cog compared to placebo, and subjects with lower cholesterols had no effect. Similarly, the gross magnitude of effect was seen in APOE-4 positive carriers compared to non-E4 carriers16. These data suggest that the subjects likely to benefit could be identified in advance with better effects hypothetically predicted to be in subjects that are E-4 carriers and subjects with higher cholesterols. Because of the post-hoc analysis of the ADCLT, interpretation of the primary end points of LEADe and other statin trials may reflect case selection stratified by baseline cholesterol levels rather than mechanisms of actions of individual products. This is very important since both simvastatin and atorvastatin are being investigated and issues between the two blood-brain barrier permeability have arisen. Secondary analyses of effect based on cholesterol panel may reveal different outcomes than primary outcome analyses developed during the conduct of these studies. If that is the case, then further studies will need to consider cholesterol patterns and genotypes in future clinical trial design in statin treatment trials for the treatment of Alzheimer's disease.