Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men
The APOE ⑀4 allele is an established risk factor for Alzheimer disease (AD), yet findings are mixed for how early its effects are manifest. One reason for the mixed results could be the presence of interaction effects with other AD risk factors. Increasing evidence indicates that testosterone may play a significant role in the development of AD. The aim of the present study was to examine the potential interaction of testosterone and APOE genotype with respect to hippocampal volume in middle
... . Methods: Participants were men from the Vietnam Era Twin Study of Aging (n ϭ 375). The mean age was 55.9 years (range 51-59). Between-group comparisons were performed utilizing a hierarchical linear mixed model that adjusted for the nonindependence of twin data. Results: A significant interaction was observed between testosterone and APOE genotype (⑀4negative vs ⑀4-positive). Those with both low testosterone (Ն1 SD below the mean) and an ⑀4positive status had the smallest hippocampal volumes, although comparisons with normal testosterone groups were not significant. However, individuals with low testosterone and ⑀4negative status had significantly larger hippocampal volumes relative to all other groups. A main effect of APOE genotype on hippocampal volume was observed, but only when the APOE-bytestosterone interaction was present. Conclusions: These findings demonstrate an interaction effect between testosterone and the APOE ⑀4 allele on hippocampal volume in middle-aged men, and they may suggest 2 low testosterone subgroups. Furthermore, these results allude to potential gene-gene interactions between APOE and either androgen receptor polymorphisms or genes associated with testosterone production. Neurology ® 2010;75:874-880 GLOSSARY AD ϭ Alzheimer disease; AR ϭ androgen receptor; BMI ϭ body mass index; CI ϭ confidence interval; ICV ϭ intracranial volume; MGH ϭ Massachusetts General Hospital; UCSD ϭ University of California, San Diego; VET ϭ Vietnam Era Twin; VETSA ϭ Vietnam Era Twin Study of Aging.