Role of circulating androgen levels in effects of apoE4 on cognitive function

Compared with apoE2 and E3, apoE4 increases the risk of cognitive impairments and of developing Alzheimer's disease (AD). ApoE4 interacts with female sex, further increasing AD risk. Previously, we showed that female Apoe^-/- mice are more susceptible to apoE4-induced cognitive deficits than male mice. Androgens protect against these deficits and apoE4 male mice are more sensitive to acute blockade of androgen receptors than apoE3 male mice. To determine the chronic effects of reduced circulating androgen levels on susceptibility to the effects of apoE4 on cognitive function in males, we castrated and sham-castrated apoE4, apoE3, and Apoe^-/- male mice and behaviorally compared them 3 months later. Castration impaired novel location recognition in apoE4, but not apoE3 or Apoe^-/-, mice. In contrast, castration impaired novel object recognition and spatial memory retention in the water maze in Apoe^-/-, but not apoE3 or apoE4, mice. On the contrary, castrated, but not sham-castrated, apoE4 mice showed improved acquisition over the first two hidden platform sessions and spatial memory retention in the first probe trial. While apoE3 and Apoe^-/- mice increased their exploratory times with the objects in the trial with the novel object, apoE4 mice did not. ApoE4 mice required more trials than apoE3 or Apoe^-/- mice to reach criterion during passive avoidance training, but castration did not modulate passive avoidance learning or memory. Thus, androgens have differential roles in object recognition and spatial learning and memory in the water maze, depending on whether or not apoE4 is present.