Alzheimer's disease (AD) is a neurodegenerative disorder affecting tens of millions of people worldwide, with women being at greater risk of developing the disease. A growing body of evidence suggests transthyretin (TTR) as an important modulator of AD pathogenesis. Aiming at providing further insight into the potential neuroprotective role of TTR and gender differences in AD, we crossed transgenic AβPPswe/PS1A246E mice with TTR-null mice and investigated both male and female AβPPswe/PS1A246E/TTR+/+, AβPPswe/PS1A246E/TTR+/-, and AβPPswe/PS1A246E/TTR-/- animals for brain amyloid-β (Aβ) levels and deposition. The levels of circulating TTR between non-transgenic and AD mice were evaluated. Decreased levels of circulating TTR in AD mice as compared to non-transgenic littermates were observed in early stages of AD-like neuropathology, but not at later stages where an opposite relationship was found. Elevated brain levels of Aβ42 were observed in AβPPswe/PS1A246E/TTR+/- female mice as compared to AβPPswe/PS1A246E/TTR+/+ female littermates; no significant differences were found among males of different TTR genotypes. We subsequently quantified the brain levels of testosterone and 17β-estradiol in these animals and verified that AβPPswe/PS1A246E/TTR+/- female mice present reduced brain levels of both hormones as compared to AβPPswe/PS1A246E/TTR+/+ females; no significant differences were detected among males of different TTR genotypes. Our results provide evidence for a gender-associated modulation of brain Aβ levels and brain sex steroid hormones by TTR, and suggest that reduced levels of brain testosterone and 17β-estradiol in female mice with TTR genetic reduction might underlie their increased AD-like neuropathology.