The apolipoprotein E (APOE) ε4 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.
To determine if the APOE ε4 allele increases susceptibility to lorazepam-induced verbal learning impairment in nondemented older adults.
A placebo-controlled crossover design.
A community-based sample of subjects.
Sixty-four cognitively intact and highly educated (>12 years) adults. Twenty-four subjects (mean age, 66.3 years) were carriers of an APOE ε4 allele (ε4 positive) and 40 (mean age, 66.0 years) were not (ε4 negative).
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.
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 ε4-negative group showed significant improvement in long-term memory, but the ε4-positive group demonstrated a persistent deficit. Subsequent analysis revealed that the poor performance at 5 hours was found in an ε4-positive subgroup with lower baseline performance.
In cognitively intact, older adults, the effect of the APOE ε4 allele is not necessarily seen in the immediate response to benzodiazepine challenge. Rather, the APOE ε4 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 ε4 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 ε4 allele and its interaction with other factors in the development of Alzheimer disease and other age-related cognitive problems.