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Sex, Apolipoprotein E  4 Status, and Hippocampal Volume in Mild Cognitive Impairment
Adam Fleisher, MD;
Michael Grundman, MD, MPH;
Clifford R. Jack, Jr, MD;
Ronald C. Petersen, PhD, MD;
Curtis Taylor, PhD;
Hyun T. Kim, MS;
Denise H. B. Schiller, BA;
Victor Bagwell, MSIT, MBA;
Drahomira Sencakova, MD;
Myron F. Weiner, MD;
Charles DeCarli, MD;
Steven T. DeKosky, MD;
Christopher H. van Dyck, MD;
Leon J. Thal, MD; for the Alzheimer’s Disease Cooperative Study
Arch Neurol. 2005;62:953-957.
Background Subjects with mild cognitive impairment (MCI) have been shown to have reduced hippocampal volumes relative to normal elderly control subjects. The presence of the apolipoprotein E  4 (APOE*E4) allele has been associated with greater hippocampal atrophy in women than in men with Alzheimer disease. This relationship has not been demonstrated in MCI.
Objective To examine the relationship between APOE genotype and hippocampal volume in men and women with MCI.
Design This study evaluated MCI in 193 subjects (86 women and 107 men) participating in a multicenter clinical trial, all of whom underwent magnetic resonance imaging at their baseline visit. We evaluated the association among the number of APOE*E4 alleles, memory performance, and hippocampal volume in men and women with tests of means and multiple linear regressions.
Results Compared with MCI subjects with no APOE*E4 alleles, women with 1 or 2 APOE*E4 alleles were found to have significantly reduced hippocampal volume, whereas men only showed a significant reduction in hippocampal volume when carrying 2 APOE*E4 alleles. Worsening of performance on a delayed word recall task (Alzheimer’s Disease Assessment Scale cognitive subscale) showed an identical pattern in association with APOE*E4 allele dose and sex. Furthermore, when controlling for memory performance on delayed word recall, the APOE*E4 effect on hippocampal volumes was attenuated in men, but remained significant in women.
Conclusion The APOE*E4 genotype status appears to have a greater deleterious effect on gross hippocampal pathology and memory performance in women than in men.
Author Affiliations: Department of Neurosciences, University of California–San Diego, La Jolla (Drs Fleisher, Taylor, and Thal, Messrs Kim and Bagwell, and Ms Schiller); Elan Corporation, San Diego, Calif (Dr Grundman); Departments of Diagnostic Radiology (Drs Jack and Sencakova) and Neurology (Dr Petersen), Mayo Clinic and Foundation, Rochester, Minn; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas (Dr Weiner); Department of Neurology, University of California–Davis, Sacramento (Dr DeCarli); Department of Neurology, University of Pittsburgh, Pittsburgh, Pa (Dr DeKosky); and Department of Psychiatry, Yale University School of Medicine, New Haven, Conn (Dr van Dyck).
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