Another Negative MCI Trial

At least 4 placebo-controlled trials of cholinesterase inhibitors* (ChEIs) have been conducted in patients with mild cognitive impairment (MCI), a likely precursor of Alzheimer's disease. And none has demonstrated a significant effect on primary outcome measures, either progression to AD or standardized, cognitive tests.

Now add another largely negative trial, the results of which are available in this week's issue of Neurology. In a multicenter, double-blind, randomized study of 778 patients with MCI, donepezil (at a maximum dosage of 10 mg/d) was no better than placebo for altering cognitive scores at 1 year. However, a small, but statistically significant difference was noted between the modified ADAS-Cog scores of donepezil- and placebo-treated patients. Other secondary measures also favored donepezil, but treated subjects were much more likely to discontinue the drug because of adverse events (18.4% vs 8.3% with placebo).

The authors speculate that standard measures of cognition, function, and global impairment may be insensitive to the more subtle, progressive changes observed in patients with MCI. In a related editorial, David Knopman of the Mayo Clinic suggests that biomarkers—like hippocampal atrophy, low CSF amyloid-beta/tau protein ratios, and APOE ε4 genotypes—may provide better endpoints in MCI trials. All have been associated with higher rates of progressive cognitive dysfunction in these patients.

N.B. The study was supported by Eisai and Pfizer. Two of the 8 authors are employees of Eisai; 2 are employees of Pfizer.

ADAS-Cog: Alzheimer's Disease Assessment Scale-cognitive subscale.

* Donepezil (Aricept; Eisai/Pfizer), rivastigmine (Exelon; Novartis), and galantamine (Razadyne; Ortho-McNeil).

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.