While tissue specific effects of selective androgen receptor modulators (SARMs) outside the brain have been reported, little is known about brain specific SARMs. Here we show that SARMs upregulate androgen receptor levels in brain following castration and antagonize impairments in hippocampus-dependent novel location recognition and spatial memory retention in apoE4 female mice. Together with the reduced androgen levels in aged men and women and the beneficial effects of androgens on brain function and pathology in Alzheimer's disease-related models, these data support the therapeutic potential of SARMs for age-related cognitive decline and Alzheimer's disease.