Extensive changes in neural tissue structure and function accompanying Alzheimer's disease (AD) suggest that intrinsic signal optical imaging can provide new contrast mechanisms and insight for assessing AD appearance and progression. In this work, we report the development of a wide-field spatial frequency domain imaging (SFDI) method for non-contact, quantitative in vivo optical imaging of brain tissue composition and function in a triple transgenic mouse AD model (3xTg). SFDI was used to generate optical absorption and scattering maps at up to 17 wavelengths from 650 to 970 nm in 20-month-old 3xTg mice (n = 4) and age-matched controls (n = 6). Wavelength-dependent optical properties were used to form images of tissue hemoglobin (oxy-, deoxy-, and total), oxygen saturation, and water. Significant baseline contrast was observed with 13-26% higher average scattering values and elevated water content (52 ± 2% vs. 31 ± 1%); reduced total tissue hemoglobin content (127 ± 9 μM vs. 174 ± 6 μM); and lower tissue oxygen saturation (57 ± 2% vs. 69 ± 3%) in AD vs. control mice. Oxygen inhalation challenges (100% oxygen) resulted in increased levels of tissue oxy-hemoglobin (ctO(2)Hb) and commensurate reductions in deoxy-hemoglobin (ctHHb), with ~60-70% slower response times and ~7 μM vs. ~14 μM overall changes for 3xTg vs. controls, respectively. Our results show that SFDI is capable of revealing quantitative functional contrast in an AD model and may be a useful method for studying dynamic alterations in AD neural tissue composition and physiology.