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Apolipoprotein E 4 Allele and Lorazepam Effects on Memory in High-Functioning Older Adults

Nunzio Pomara, MD; Lisa Willoughby, PhD; Keith Wesnes, PhD; David J. Greenblatt, MD; John J. Sidtis, PhD

Arch Gen Psychiatry. 2005;62:209-216.

Context  The apolipoprotein E (APOE) 4 allele has been implicated as a significant risk factor in the development of late-onset Alzheimer disease, but the evidence of cognitive sequelae in healthy individuals has been mixed.

Objective  To determine if the APOE 4 allele increases susceptibility to lorazepam-induced verbal learning impairment in nondemented older adults.

Design  A placebo-controlled crossover design.

Setting  A community-based sample of subjects.

Participants  Sixty-four cognitively intact and highly educated (>12 years) adults. Twenty-four subjects (mean age, 66.3 years) were carriers of an APOE 4 allele (4 positive) and 40 (mean age, 66.0 years) were not (4 negative).

Interventions  All subjects received a single oral dose of placebo and lorazepam (0.5 and 1.0 mg) 1 week apart.

Main Outcome Measure  We used the Buschke Selective Reminding Test to assess verbal learning during a 5-hour period after placebo or lorazepam administration.

Results  We found a time-related, dose-dependent effect of lorazepam, with long-term recall generally decreasing with higher doses of lorazepam at up to 2.5 hours. At 5 hours, the 4-negative group showed significant improvement in long-term memory, but the 4-positive group demonstrated a persistent deficit. Subsequent analysis revealed that the poor performance at 5 hours was found in an 4-positive subgroup with lower baseline performance.

Conclusions  In cognitively intact, older adults, the effect of the APOE 4 allele is not necessarily seen in the immediate response to benzodiazepine challenge. Rather, the APOE 4 allele appears to affect the carrier’s ability to recover from a cognitive challenge in a normal fashion, at least in a subgroup of subjects with relatively low baseline performance. This suggests that although carrying an APOE 4 allele increases the risk for cognitive toxic effects, allele status alone is not a sufficient predictor of such effects. Studying the response to and the recovery from cognitive challenges may provide insights into the role of the APOE 4 allele and its interaction with other factors in the development of Alzheimer disease and other age-related cognitive problems.

Author Affiliations: Geriatric Psychiatry Program, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY (Drs Pomara, Willoughby, and Sidtis); Department of Psychiatry, New York University School of Medicine, New York (Drs Pomara and Sidtis); Cognitive Drug Research, Ltd, Reading, England (Dr Wesnes); and Department of Pharmacology, Tufts University, Boston, Mass (Dr Greenblatt).

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