Gender, Sex Steroid Hormones, and Alzheimer's Disease

Overview

Journal Horm Behav

Specialties Endocrinology
Psychology
Social Sciences

Date 2012 May 5

PMID 22554955

Citations 98

Authors

Rebekah S Vest

Christian J Pike

Affiliations

Soon will be listed here.

Abstract

Age-related loss of sex steroid hormones is a established risk factor for the development of Alzheimer's disease (AD) in women and men. While the relationships between the sex steroid hormones and AD are not fully understood, findings from both human and experimental paradigms indicate that depletion of estrogens in women and androgens in men increases vulnerability of the aging brain to AD pathogenesis. We review evidence of a wide range of beneficial neural actions of sex steroid hormones that may contribute to their hypothesized protective roles against AD. Both estrogens and androgens exert general neuroprotective actions relevant to a several neurodegenerative conditions, some in a sex-specific manner, including protection from neuron death and promotion of select aspects of neural plasticity. In addition, estrogens and androgens regulate key processes implicated in AD pathogenesis, in particular the accumulation of β-amyloid protein. We discuss evidence of hormone-specific mechanisms related to the regulation of the production and clearance of β-amyloid as critical protective pathways. Continued elucidation of these pathways promises to yield effective hormone-based strategies to delay development of AD.

Citing Articles

Exploring sex differences in Alzheimer's disease: a comprehensive analysis of a large patient cohort from a memory unit.

Rosende-Roca M, Garcia-Gutierrez F, Cantero-Fortiz Y, Alegret M, Pytel V, Canabate P Alzheimers Res Ther. 2025; 17(1):27.

PMID: 39844303 PMC: 11753069. DOI: 10.1186/s13195-024-01656-9.

Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease.

Biel D, Suarez-Calvet M, Dewenter A, Steward A, Roemer S, Dehsarvi A EMBO Mol Med. 2025; 17(2):235-248.

PMID: 39794447 PMC: 11822105. DOI: 10.1038/s44321-024-00190-3.

Guidelines for the standardization of pre-analytical variables for salivary biomarker studies in Alzheimer's disease research: An updated review and consensus of the Salivary Biomarkers for Dementia Research Working Group.

Ng T, Udeh-Momoh C, Lim M, Gleerup H, Leifert W, Ajalo C Alzheimers Dement. 2024; 21(2):e14420.

PMID: 39737743 PMC: 11848381. DOI: 10.1002/alz.14420.

Risk of glaucoma to subsequent dementia or cognitive impairment: a systematic review and meta-analysis.

Wang X, Chen W, Zhao W, Miao M Aging Clin Exp Res. 2024; 36(1):172.

PMID: 39162899 PMC: 11335947. DOI: 10.1007/s40520-024-02811-w.

Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates Detrusor Hyperactivity with Impaired Contractility via Transient Potential Vanilloid Channels: A Rat Model for Ovarian Hormone Deficiency.

Chueh K, Juan T, Lu J, Wu B, Lin R, Mao J Int J Mol Sci. 2024; 25(9).

PMID: 38732143 PMC: 11084446. DOI: 10.3390/ijms25094927.

References

King D, Arendash G, Crawford F, Sterk T, Menendez J, Mullan M . Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer's disease. Behav Brain Res. 1999; 103(2):145-62. DOI: 10.1016/s0166-4328(99)00037-6. View

Rocca W, Amaducci L, Schoenberg B . Epidemiology of clinically diagnosed Alzheimer's disease. Ann Neurol. 1986; 19(5):415-24. DOI: 10.1002/ana.410190502. View

Kaufman J, Vermeulen A . The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005; 26(6):833-76. DOI: 10.1210/er.2004-0013. View

Yu W . Sex difference in neuronal loss induced by axotomy in the rat brain stem motor nuclei. Exp Neurol. 1988; 102(2):230-5. DOI: 10.1016/0014-4886(88)90098-2. View

Jaffe A, Toran-Allerand C, Greengard P, Gandy S . Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem. 1994; 269(18):13065-8. View

Gore A . Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems. Front Neuroendocrinol. 2008; 29(3):358-74. PMC: 2702520. DOI: 10.1016/j.yfrne.2008.02.002. View

Petanceska S, Nagy V, Frail D, Gandy S . Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain. Exp Gerontol. 2000; 35(9-10):1317-25. DOI: 10.1016/s0531-5565(00)00157-1. View

Kawashima S, Takagi K . Role of sex steroids on the survival, neuritic outgrowth of neurons, and dopamine neurons in cultured preoptic area and hypothalamus. Horm Behav. 1994; 28(4):305-12. DOI: 10.1006/hbeh.1994.1026. View

Fleisher A, Grundman M, Jack Jr C, Petersen R, Taylor C, Kim H . Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment. Arch Neurol. 2005; 62(6):953-7. DOI: 10.1001/archneur.62.6.953. View

10.

Gillies G, Murray H, Dexter D, McArthur S . Sex dimorphisms in the neuroprotective effects of estrogen in an animal model of Parkinson's disease. Pharmacol Biochem Behav. 2004; 78(3):513-22. DOI: 10.1016/j.pbb.2004.04.022. View

11.

Xiao Z, Sun L, Liu Y, Zhang J, Huang J . Estrogen regulation of the neprilysin gene through a hormone-responsive element. J Mol Neurosci. 2009; 39(1-2):22-6. DOI: 10.1007/s12031-008-9168-1. View

12.

Ramsden M, Nyborg A, Murphy M, Chang L, Stanczyk F, Golde T . Androgens modulate beta-amyloid levels in male rat brain. J Neurochem. 2003; 87(4):1052-5. DOI: 10.1046/j.1471-4159.2003.02114.x. View

13.

Johnson M, Day A, Ho C, Walker Q, Francis R, Kuhn C . Androgen decreases dopamine neurone survival in rat midbrain. J Neuroendocrinol. 2010; 22(4):238-47. PMC: 3025447. DOI: 10.1111/j.1365-2826.2010.01965.x. View

14.

Hirata-Fukae C, Li H, Hoe H, Gray A, Minami S, Hamada K . Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res. 2008; 1216:92-103. DOI: 10.1016/j.brainres.2008.03.079. View

15.

MacLusky N, Hajszan T, Leranth C . Effects of dehydroepiandrosterone and flutamide on hippocampal CA1 spine synapse density in male and female rats: implications for the role of androgens in maintenance of hippocampal structure. Endocrinology. 2004; 145(9):4154-61. DOI: 10.1210/en.2004-0477. View

16.

Amtul Z, Wang L, Westaway D, Rozmahel R . Neuroprotective mechanism conferred by 17beta-estradiol on the biochemical basis of Alzheimer's disease. Neuroscience. 2010; 169(2):781-6. DOI: 10.1016/j.neuroscience.2010.05.031. View

17.

Farrer L, Cupples L, Haines J, Hyman B, Kukull W, Mayeux R . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997; 278(16):1349-56. View

18.

Gouras G, Xu H, GROSS R, Greenfield J, Hai B, Wang R . Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci U S A. 2000; 97(3):1202-5. PMC: 15568. DOI: 10.1073/pnas.97.3.1202. View

19.

Carroll J, Rosario E . The potential use of hormone-based therapeutics for the treatment of Alzheimer's disease. Curr Alzheimer Res. 2012; 9(1):18-34. DOI: 10.2174/156720512799015109. View

20.

Yao M, Nguyen T, Rosario E, Ramsden M, Pike C . Androgens regulate neprilysin expression: role in reducing beta-amyloid levels. J Neurochem. 2008; 105(6):2477-88. DOI: 10.1111/j.1471-4159.2008.05341.x. View