In the Look AHEAD trial, randomization to Intensive Lifestyle Intervention (ILI) or Diabetes Support and Education (DSE) did not result in differences in cognitive outcomes. However, menopause and APOE genotype are factors that affect the response to this intervention. The effect of this intervention on a single cognitive assessment was examined in 3 groups of women: premenopausal or <5 years postmenopausal (N = 594), within 5-10 years (n = 388), and ≥10 years postmenopausal (n = 963), and as a function of continuous years since menopause. The late postmenopausal group in the ILI had worse composite z-scores compared to those in the DSE, whereas the younger premenopausal or early postmenopausal women in the ILI had better composite z-scores than the DSE. A significant interaction between years since menopause and intervention arm, but not baseline age, was observed on executive function domains. ILI appeared only to benefit cognitive function among non-APOE4 carriers during premenopause or early postmenopause. These findings emphasize the importance of assessing menopause and APOE status to understand how weight loss impacts cognition.Copyright © 2020 Elsevier Inc. All rights reserved.