NEW ORLEANS — High-dose atorvastatin in Alzheimer's disease patients slowed progressive cognitive deterioration and improved depressive symptoms in a first-of-its-kind small, randomized, double-blind trial, D. Larry Sparks, Ph.D., said at the annual scientific sessions of the American Heart Association.
The definitive word on the efficacy of high-dose statin therapy for the cognitive and behavioral manifestations of Alzheimer's dementia must await completion of two ongoing large multicenter clinical trials, but the results of this single-center 1-year pilot study are certainly promising, said Dr. Sparks, senior scientist and head of the Ralph and Muriel Roberts Laboratory for Neurodegenerative Research at the Sun Health Research Institute, Sun City, Ariz.
He reported on 46 patients with mild-to-moderate Alzheimer's disease who completed 1 year on 80 mg/day of atorvastatin or placebo in addition to whatever cholinesterase inhibitors they were already on at randomization.
Primary outcomes in the study, were change in the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), both administered quarterly. The study was sponsored by the Institute for the Study of Aging and Pfizer Inc.
From a mean baseline score of 20 on the ADAS-cog, both the atorvastatin and placebo groups showed deterioration at 3 months. Thereafter, scores in the statin group stabilized, but the placebo group continued to deteriorate by about 1 point per quarter, so that at 1 year the atorvastatin group had a mean 3.5-point superior score on this instrument.
Mean ADCS-CGIC scores declined with time in both groups. However, the rate of decline was consistently steeper in the placebo arm, with the between-group differences missing statistical significance by the barest of margins at both 9 and 12 months, Dr. Sparks continued.
Mean scores on the Geriatric Depression Scale improved from 6 to 4 over the course of the year in the atorvastatin group while deteriorating to 8 in the placebo arm—a significant between-group difference.
Scores on the 10-item Neuropsychiatric Inventory declined from a baseline of 7.5 to 9 in the atorvastatin group and to 16 in the placebo group at 1 year.
Mean scores on the Mini-Mental State Examination remained stable in the atorvastatin group—20.8 at baseline and 20.4 at 1 year—while declining to 18 in the placebo group.
Performance on the ADCS Activities of Daily Living scale at 6 and 12 months didn't show any strong between-group differences.
Serum levels of superoxide dismutase and glutathione peroxidase activity were unchanged by high-dose atorvastatin; however, mean circulating ceruloplasmin levels were reduced 10%–15% at various time points, compared with placebo.
Dr. Sparks noted that animal studies suggest cholesterol in the brain plays a key role in production of β-amyloid, the putative neurotoxin believed to precipitate Alzheimer's disease. But while the marked reductions in circulating total, LDL, and VLDL cholesterol achieved with high-dose atorvastatin in the study are consistent with a lipid-lowering mechanism for the apparent cognitive and affective benefits, statins also improve vascular endothelial function and have antiinflammatory effects that might be relevant.
The impetus for this pilot randomized trial as well as the ongoing far larger ones stems in large part from multiple hypothesis-generating epidemiologic studies that have reported an association between lipid-lowering drug therapy and reduced rates and/or slower progression of Alzheimer's disease.