Associations Between Midlife Menopausal Hormone Therapy Use, Incident Diabetes, and Late Life Memory in the Wisconsin Longitudinal Study

Article type: Research Article

Authors: Williams, Victoria J.^{a; b; *} | Koscik, Rebecca^{a; b; c} | Sicinski, Kamil^d | Johnson, Sterling C.^{a; b; c; e; f} | Herd, Pamela^f | Asthana, Sanjay^{a; b; c; e; f}

Affiliations: [a] Department of Medicine, Division of Geriatrics and Gerontology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI, USA | [b] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin Schoolof Medicine and Public Health, Madison, WI, USA | [c] Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [d] Center for Demography of Health and Aging, University of Wisconsin at Madison, Madison, WI, USA | [e] Geriatric Research Education and Clinical Center, William S. Middleton Veterans Hospital, Madison, WI, USA | [f] McCourt School of Public Policy, Georgetown University, Washington, DC, USA

Correspondence: [*] Correspondence to: Victoria J. Williams, PhD, Assistant Professor, CHS, University of Wisconsin – Madison, School of Medicine and Public Health, 3330 University Avenue, Suite 200, Madison, WI 53705, USA. Tel.: +1 608 265 3091; E-mail: vwilliams@medicine.wisc.edu.

Abstract: Background:Prior research suggests a link between menopausal hormone therapy (MHT) use, memory function, and diabetes risk. The menopausal transition is a modifiable period to enhance long-term health and cognitive outcomes, although studies have been limited by short follow-up periods precluding a solid understanding of the lasting effects of MHT use on cognition. Objective:We examined the effects of midlife MHT use on subsequent diabetes incidence and late life memory performance in a large, same-aged, population-based cohort. We hypothesized that the beneficial effects of MHT use on late life cognition would be partially mediated by reduced diabetes risk. Methods:1,792 women from the Wisconsin Longitudinal Study (WLS) were included in analysis. We employed hierarchical linear regression, Cox regression, and causal mediation models to test the associations between MHT history, diabetes incidence, and late life cognitive performance. Results:1,088/1,792 women (60.7%) reported a history of midlife MHT use and 220/1,792 (12.3%) reported a history of diabetes. MHT use history was associated with better late life immediate recall (but not delayed recall), as well as a reduced risk of diabetes with protracted time to onset. Causal mediation models suggest that the beneficial effect of midlife MHT use on late life immediate recall were at least partially mediated by diabetes risk. Conclusion:Our data support a beneficial effect of MHT use on late life immediate recall (learning) that was partially mediated by protection against diabetes risk, supporting MHT use in midlife as protective against late life cognitive decline and adverse health outcomes.

Keywords: Adult onset diabetes mellitus, Alzheimer’s disease, estrogen, immediate memory, mediation, menopause

DOI: 10.3233/JAD-221240

Journal: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 727-741, 2023