Transthyretin (TTR) is a plasma and cerebrospinal fluid carrier for thyroxine and retinol, described also to sequester the amyloid beta peptide. TTR levels have been described as decreased in the cerebrospinal fluid of patients with Alzheimer's disease. In order to investigate the role of TTR in learning and memory, we studied young adult and old TTR-null 129/Sv mice for cognitive performance. In the absence of TTR, 5-month-old mice display spatial reference memory impairment when compared to age-matched wild-type mice. Interestingly, while aging in wild-type mice is associated with a worsening reference memory performance, TTR-null mice show no further impairment with increasing age. As a result, no significant differences were found in this spatial reference task in old mice. Our data show that the absence of TTR seems to accelerate the poorer cognitive performance normally associated with aging.