Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial

Context – Recent evidence suggests that treatment of mild‐to‐moderate Alzheimer's disease (AD) with atorvastatin provides significant benefit on the Alzheimer Disease Assessment Scale‐Cognitive (ADAS‐cog) after 6 months. Objective – To determine if benefit on ADAS‐cog performance produced by atorvastatin is influenced by severity of cognitive impairment, circulating cholesterol levels, or apolipoprotein E genotype. Design – A double‐blind, placebo‐controlled, randomized (1:1) trial with a 1‐year exposure to atorvastatin calcium or placebo. Setting – A single‐site study at the clinical research center of the Sun Health Research Institute. Participants – Ninety‐eight individuals with mild‐to‐moderate AD (MMSE score of 12–28) provided informed consent, and 67 were randomized. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of many other medications in the treatment of co‐morbidities. Participants using cholesterol‐lowering medications or being treated for major depression or a psychiatric condition were excluded. Intervention – Once daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo. Main outcome measures – A primary outcome measure was change ADAS‐cog sub‐scale score. Secondary outcome measures included scores on the MMSE, and circulating cholesterol levels. The Apolipoprotein E genotype was established for each participant. Results – A significant positive effect on ADAS‐cog performance occurred after 6 months of atorvastatin therapy compared with placebo. This positive effect was more prominent among individuals entering the trial with, (i) higher MMSE scores, (ii) cholesterol levels above 200 mg/dl or (iii) if they harbored an apolipoprotein‐E‐4 allele compared with participants not responding to atorvastatin treatment. Individuals in the placebo group tended to experience more pronounced deterioration if their cholesterol levels exceeded 200 mg/dl or they harbored an apolipoprotein‐E‐4 allele. Conclusion – Atorvastatin therapy may be of benefit in the treatment of mild‐to‐moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment, an individual's apolipoprotein E genotype or whether the patient exhibits elevated cholesterol levels.