Double-Blind Crossover Study of the Cognitive Effects of Lorazepam in Healthy Apolipoprotein E (APOE)-ε4 Carriers

Objective: To examine cognitive effects of pharmacologically induced somnolence in cognitively normal carriers and noncarriers of the apolipoprotein E (APOE)-e4 allele, a common Alzheimer’s disease susceptibility gene.

Method: Between December 2005 and July 2007, healthy and cognitively normal carriers of the APOE-e4 allele (heterozygotes; n = 18) and noncarriers (n = 18), 50 to 65 years old, participated in a double-blind crossover study of cognitive function before, 2.5 hours after, and 5 hours after administration of 2 mg oral lorazepam or placebo. Main outcome measures included the Groton Maze Learning Test (GMLT) for executive functioning and visuospatial working memory, the Rey Auditory-Verbal Learning Test (AVLT) for verbal memory, and the one-back test for attention and simple working memory.

Results: At 2.5 hours after lorazepam administration, GMLT total errors score (P = .04), AVLT long-term memory (P = .01), and AVLT percent recall (P = .005) reflected worse performance in heterozygotes. By multivariate analysis, the combined set of all 6 measures for heterozygotes versus noncarriers yielded P = .003 for 2.5 hours and P = .58 for 5 hours. No differences were observed for somnolence, speed, attention, or simple working memory at any time points.

Conclusions: Despite comparable levels of associated somnolence, lorazepam appears to diminish verbal and visuospatial memory more in healthy late-middle-aged heterozygotes than in noncarriers, whereas attention and reaction time are similarly affected in both. Additional studies are needed to determine whether substantial lorazepam-induced memory detriments predict subsequent onset of cognitive decline and conversion to mild cognitive impairment or Alzheimer’s disease. Clinicians should be aware of the potential for cognitive decline with lorazepam in healthy late-middle-aged individuals, especially those at a higher risk for Alzheimer’s disease.

Trial Registration: clinicaltrials.gov Identifier: NCT00586430

Submitted: July 25, 2008; accepted October 9, 2008.

Online ahead of print: June 30, 2009.

Corresponding author: Cynthia M. Stonnington, MD, Division of Adult Psychiatry, Mayo Clinic, 13400 East Shea Blvd, Scottsdale, AZ 85259 ([email protected]).