Lifetime Exposure to Estrogen Preserves Brain Health in Older Women in the IGNITE study

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BACKGROUND: Two-thirds of AD patients are women, and aging-related hormonal changes may contribute to these sex differences. Lower lifetime exposure to estrogen, a neuroprotectant, is associated with AD-related brain atrophy. Estrogen-based therapies are associated with better brain health, including preserved brain volume in areas that atrophy with aging. We investigated whether hormone-based medications (birth control (BC), menopausal hormone therapy (MHT)) were associated with structural neuroimaging markers of aging and Alzheimer's disease. We hypothesized that timing of hormone-based therapies would be associated with larger brain volume and greater cortical thickness in older women in temporo-limbic regions. METHOD: We investigated baseline associations in Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), a 12-month, multi-site, randomized aerobic exercise trial in 459 female participants aged 65-80. We used SPM12 and CAT12 software to process 3D-T1 MPRAGE images, and conducted voxel-based (VBM-gray matter volume) and surface-based morphometry (SBM-thickness) to investigate voxel-wise differences between individuals that had a history of a) BC use vs. no BC use; b) MHT use vs. no MHT use and c) MHT use (no BC) vs. no MHT use (no BC), accounting for age, education, study site, and APOE4 carrier status. RESULT: In the VBM analysis, BC use (average start age 22) was associated with larger left inferior frontal gyrus volume (cluster k=2613, FWE corrected p -value= 0.004, Figure 1). BC timing (starting age, duration) did not add significantly to the models. In the SBM analysis, combined BC and MHT use was associated with a thicker left middle temporal cortex (vertices = 496, FWE corrected p -value=0.019). Interestingly, when looking at MHT use without the use of BC earlier in life, there were still brain benefits of increased cortical thickness in the right lingual gyrus (vertices=459, FWE corrected p -value=0.032). CONCLUSION: Our results support prior evidence that lifetime estrogen exposure is important for healthy brain aging, particularly with regard to brain volume. These findings have clinical implications for estrogen-based therapies throughout the lifespan. Understanding sex differences in AD is critical for developing sex-specific prevention strategies and treatments as part of a precision medicine approach.

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