Double-blind crossover study of the cognitive effects of lorazepam in healthy apolipoprotein E (APOE)-epsilon4 carriers.
OBJECTIVE
To examine cognitive effects of pharmacologically induced somnolence in cognitively normal carriers and noncarriers of the apolipoprotein E (APOE)-epsilon4 allele, a common Alzheimer's disease susceptibility gene.


METHODS
Between December 2005 and July 2007, healthy and cognitively normal carriers of the APOE-epsilon4 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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00586430.
Stonnington
Cynthia M
CM
Division of Adult Psychiatry, Mayo Clinic, Scottsdale, AZ 85259, USA. stonnington.cynthia@mayo.edu
Snyder
Peter J
PJ
Hentz
Joseph G
JG
Reiman
Eric M
EM
Caselli
Richard J
RJ
D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000139:chemically induced / Q000209:etiology; D053327:Apolipoprotein E4 / Q000235:genetics*; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008140:Lorazepam / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced; D008875:Middle Aged; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D014706:Verbal Learning / Q000187:drug effects
D053327:Apolipoprotein E4; D006993:Hypnotics and Sedatives; D008140:Lorazepam