Atorvastatin for the treatment of mild to moderate Alzheimer disease
Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, et al. ;
Commented by , 16 Jun 2005
Aim of the study
To determine if treatment with atorvastatin affects the cognitive, functional, behavioral and global decline in patients with possible or probable mild to moderate AD.
Method
Single site, double-blind randomized (1:1) trial comparing atorvastatin 80mg a day to placebo over one year in mild to moderate AD defined as Mini Mental State Examination (MMSE) scores of 12 to 28. Patients could have been on a cholinesterase inhibitor, at a stable dose for at least 3 months.
Primary outcomes were changes in the Alzheimer Disease Assessment Scale – cognitive subscale (ADAS-cog) and the Clinical Global Impression of Change (CGIC). Secondary outcomes included the MMSE, the Geriatric Depression Scale (GDS), the NeuroPsychiatric Inventory (NPI), the Alzheimer Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL).
Tertiary outcomes included total, LDL and VLDL cholesterol levels. The primary method of statistical analysis was analysis of covariance using the last observation carried forward.
Results
Out of 71 subjects randomized, 63 completed the 3-month visit and were considered evaluable. Circulating levels of cholesterol were reduced by atorvastatin. Significant differences were found in favor of atorvastatin for GDS and ADAS-cog at 6 months, with a positive trend at 12 months for ADAS-cog, CGIC, NPI.
Professor Gauthier's comments
It is logical to test a statin considering the epidemiological evidence for an increased risk of AD with elevated circulating cholesterol levels, at least in mid-life, and a protective effect of statins vs AD, at least in some studies. More recent results suggest that high total cholesterol levels in late life are associated with a reduced risk of dementia (ref. 1). There may thus be an age-specific importance of cholesterol levels in the development of the pathology of AD. It is thus possible that statins may be more effective in mid-life, or in the pre-dementia stages of AD. A limitation in placebo-controlled statin therapeutic studies is that patients must be excluded if clinically significant hyperlipidemia if present at screening.
The study was state-of-the-art as a pilot, looking at the various domains of dementia with reliable instruments. The trends for a lower decline in atorvastatin-treated patients support the need for a larger multicentre trial.
It is unclear whether the primary analysis for efficacy should be done in completers rather than last observation carried forward (LOCF), where early drop-outs can create a bias. Stable dose of a cholinesterase inhibitor with or without memantine is now inescapable in one year or longer disease-modification studies; the length of treatment of these symptomatic drugs matters – probably 6 months are required to get over the initial improvement phase and show a stable decline, "shifted to the right".
The duration of the double-blind treatment phase in mild to moderate patients should likely be longer in order to pick up a noticeable decline.
Reference
1. Mielke et al. High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 2005; 64; 1689-1695