Apolipoprotein E epsilon4 allele and lorazepam effects on memory in high-functioning older adults.
BACKGROUND
The apolipoprotein E (APOE) epsilon4 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 epsilon4 allele increases susceptibility to lorazepam-induced verbal learning impairment in nondemented older adults.


METHODS
A placebo-controlled crossover design.


METHODS
A community-based sample of subjects.


METHODS
Sixty-four cognitively intact and highly educated (>12 years) adults. Twenty-four subjects (mean age, 66.3 years) were carriers of an APOE epsilon4 allele (epsilon4 positive) and 40 (mean age, 66.0 years) were not (epsilon4 negative).


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


METHODS
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 epsilon4-negative group showed significant improvement in long-term memory, but the epsilon4-positive group demonstrated a persistent deficit. Subsequent analysis revealed that the poor performance at 5 hours was found in an epsilon4-positive subgroup with lower baseline performance.


CONCLUSIONS
In cognitively intact, older adults, the effect of the APOE epsilon4 allele is not necessarily seen in the immediate response to benzodiazepine challenge. Rather, the APOE epsilon4 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 epsilon4 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 epsilon4 allele and its interaction with other factors in the development of Alzheimer disease and other age-related cognitive problems.
Pomara
Nunzio
N
Geriatric Psychiatry Program, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA. Pomara@nki.rfmh.org
Willoughby
Lisa
L
Wesnes
Keith
K
Greenblatt
David J
DJ
Sidtis
John J
JJ
D000368:Aged / Q000502:physiology*; D000375:Aging / Q000235:genetics*; D000483:Alleles; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005820:Genetic Testing; D005838:Genotype; D015577:Geriatric Assessment; D006801:Humans; D008140:Lorazepam / Q000009:adverse effects / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000175:diagnosis; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D014706:Verbal Learning / Q000187:drug effects*
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008140:Lorazepam