Endocrine Dyscrasia in the Etiology and Therapy of Alzheimer’s Disease

Article type: Review Article

Authors: Butler, Tracy^a | Tey, Sin-Ruow^b | Galvin, James E.^c | Perry, George^d | Bowen, Richard L.^e | Atwood, Craig S.^{f; g; *}

Affiliations: [a] Department of Radiology, Brain Health Imaging Institute, Weill Cornell Medicine, New York, NY, USA | [b] JangoBio, LLC, Division of Cell Biology, Fitchburg, WI, USA | [c] Departments of Neurology and Psychiatry, Comprehensive Center for Brain Health, University of Miami, Miller School of Medicine, Boca Raton, FL, USA | [d] Department of Neuroscience, Development and Regenerative Biology, University of Texas at San Antonio, San Antonio, TX, USA | [e] OTB Research, Charleston, SC, USA | [f] Geriatric Research, Education and Clinical Center, Veterans Administration Hospital and Department of Medicine, University of Wisconsin, Madison, WI, USA | [g] School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia

Correspondence: [*] Correspondence to: Craig S. Atwood, PhD, University of Wisconsin-Madison School of Medicine and Public Health, Wm S. Middleton Memorial VA (GRECC 11G), 2500 Overlook Terrace, Madison, WI 53705, USA. Tel.: +1 608 256 1901, Ext. 11664; E-mail: [email protected].

Abstract: The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer’s disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD.

Keywords: Alzheimer’s disease, amyloid-β , andropause, cell cycle, cognition, endocrine dyscrasia, 17β-estradiol, GnRH analogues, gonadotropins, hypothalamic-pituitary-gonadal axis, menopause, neurodegeneration, neuropathology, progesterone, tau

DOI: 10.3233/JAD-240334

Journal: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 705-713, 2024