Do APOE4+ women stand to benefit from menopausal hormone therapy? Piloting an experimental therapeutics approach to accelerate progress in dementia prevention research.
2023 Award: $44,875
Menopausal hormone replacement therapy (HRT) is not currently recommended to reduce risk for Alzheimer’s disease. However, emerging evidence suggests women who are APOE-4 carriers (the “Alzheimer’s gene”) may benefit from early initiation of HRT during the menopausal transition to reduce Alzheimer’s risk. We will pilot a short-term randomized, placebo-controlled trial to determine the potential efficacy of perimenopausal estrogen treatment to improve cognitive and brain markers associated with Alzheimer’s Disease in APOE-4 carriers compared to non-carriers.
Need/Problem: Menopausal hormone replacement therapy (HRT) is not currently recommended to reduce risk for Alzheimer’s disease. However, emerging evidence suggests women who are APOE-4 carriers (the “Alzheimer’s gene”) may benefit from early initiation of HRT during the menopausal transition to reduce Alzheimer’s risk. Randomized, placebo-controlled trials are needed to confirm the efficacy of perimenopausal HRT to offset Alzheimer’s risk in women with the APOE-4 allele. Without such research, at-risk women may miss this critical window to access a readily available, relatively low-risk treatment to mitigate long-term risk for Alzheimer’s disease.
Grant Summary: We will examine the effects of short-term perimenopausal estrogen treatment vs. placebo on cognitive and brain markers of Alzheimer’s risk in women who carry the APOE-4 allele vs. those who do not. This grant will serve as a supplement to an existing randomized, placebo-controlled trial examining the brain mechanisms by which perimenopausal estrogen treatment improves mood and psychiatric symptoms.
Goals and Projected Outcomes: This study will provide preliminary data on the efficacy of perimenopausal estrogen treatment to improve Alzheimer’s-related cognitive and brain biomarkers in APOE-4 carriers. The findings of this study will serve as preliminary data to support an early career training grant focused on the efficacy of menopausal interventions to mitigate Alzheimer’s risk in susceptible women.
Melissa Walsh, PhD
Grant Details: Menopause overlaps with the prodromal period of Alzheimer’s Disease (AD) progression, and the decline in estrogen is thought to accelerate the development of AD-related brain disease. Menopausal hormone replacement therapy (HRT) may mitigate AD risk by extending the window of normal brain estrogen signaling. To date, studies have yielded contradictory findings regarding the cognitive benefit of HRT, but women with certain risk factors may benefit. APOE-4 is the greatest genetic risk factor for AD, and it is linked to higher AD risk in women and accelerated AD-related brain disease progression during the menopause transition. A recent study showed early initiation of HRT during the menopause transition was associated with improved AD-related cognitive and brain biomarkers, but only in APOE-4 carriers. Thus, APOE-4 carriers may benefit from perimenopausal HRT to reduce AD risk. However, randomized, placebo-controlled trials (RCT) are needed to determine the cognitive and brain benefit of perimenopausal HRT in APOE-4 carriers. We will conduct a pilot RCT examining the effects of three-week estrogen treatment on AD-related biomarkers in perimenopausal APOE-4 carriers vs. non-carriers. Results will provide preliminary data to support future funding examining the efficacy of perimenopausal treatment to reduce AD risk in susceptible women.
