Lifetime Estrogen Exposure and Domain-Specific Cognitive Performance: Results from the IGNITE Study

Amber Watts ^1,2* Shannon D Donofry ^3,4 Hayley S Ripperger ³ Nicole Eklund ⁵ Lu Wan ^3,6 Chaeryon Kang ⁷ George Andre Grove ³ Lauren Oberlin ^6,8 Swathi Gujral ⁷ Eric Dennis Vidoni ² Jeff Burns ² Edward McAuley ⁹ Charles H. Hillman ¹⁰ Arthur F. Kramer ¹⁰ M. Ilyas Kamboh ³ Kirk I. Erickson ^3,6*

• ¹ University of Kansas, Lawrence, United States
• ² University of Kansas Medical Center, Kansas City, Kansas, United States
• ³ University of Pittsburgh, Pittsburgh, Pennsylvania, United States
• ⁴ RAND Corportation, Pittsburgh, United States
• ⁵ Boston University School of Medicine, Boston, United States
• ⁶ AdventHealth Research Institute, Orlando, United States
• ⁷ School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
• ⁸ Psychiatry, Weill Cornell Medicine, New York, United States
• ⁹ University of Illinois at Urbana-Champaign, Champaign, Illinois, United States
• ¹⁰ Northeastern University, Boston, Massachusetts, United States

Introduction: Disruptions in estrogen exposure (i.e., surgically induced menopause) have been linked to poorer cognitive aging and dementia risk. Hormone therapy use (e.g., birth control, menopausal hormone therapy) has shown mixed associations with cognitive performance, possibly due to limited cognitive test batteries. To address previous inconsistencies, we investigated baseline data from Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE). We hypothesized that 1) oophorectomy prior to natural menopause would be associated with poorer cognitive performance, 2) timing and duration of birth control and menopausal hormone therapy would influence associations with cognitive performance, and 3) APOE4 carrier status would interact with oophorectomy and hormone therapy to influence cognitive performance. Methods: In 461 postmenopausal females (M age = 69.6) we assessed oophorectomy and hormone therapy use to examine associations with the Montreal Cognitive Assessment (MoCA) and factor-analytically derived composite scores for episodic memory, processing speed, working memory, executive function/attentional control, and visuospatial processing. Results: Hypothesis 1) We did not observe associations between oophorectomy prior to natural menopause and poorer cognitive performance. However, hormone therapy use, started on average within two years of oophorectomy, was associated with better episodic memory (β = 0.106, p = 0.02), working memory (β = 0.120, p = 0.005), and visuospatial processing (β = 0.095, p = 0.03). Hypothesis 2) Birth control use was associated with better performance on the MoCA (β = 0.093, p = 0.04), working memory (β = 0.102, p = 0.02), and executive function/attentional control (β = 0.103, p = 0.02). However, duration and timing of birth control and menopausal hormone therapy were not associated with cognitive performance. Hypothesis 3) We did not observe significant interactions between APOE4 status and oophorectomy or hormone therapy in their associations with cognitive performance. Discussion: Our results suggest exposure to estrogen during adulthood, specifically birth control and hormone therapy among women undergoing pre-menopausal oophorectomy, benefits cognitive function in older adulthood. Our comprehensive cognitive battery allowed us to examine cognitive function with a high degree of granularity. Future work should evaluate causal mechanisms of associations between lifetime estrogen exposure and later life cognitive function.