Mechanisms of Sex Differences in Alzheimer's Disease

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2024 Feb 25

PMID 38402606

Authors

Chloe Lopez-Lee

Eileen Ruth S Torres

Gillian Carling

Li Gan

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) and the mechanisms underlying its etiology and progression are complex and multifactorial. The higher AD risk in women may serve as a clue to better understand these complicated processes. In this review, we examine aspects of AD that demonstrate sex-dependent effects and delve into the potential biological mechanisms responsible, compiling findings from advanced technologies such as single-cell RNA sequencing, metabolomics, and multi-omics analyses. We review evidence that sex hormones and sex chromosomes interact with various disease mechanisms during aging, encompassing inflammation, metabolism, and autophagy, leading to unique characteristics in disease progression between men and women.

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References

Oveisgharan S, Arvanitakis Z, Yu L, Farfel J, Schneider J, Bennett D . Sex differences in Alzheimer's disease and common neuropathologies of aging. Acta Neuropathol. 2018; 136(6):887-900. PMC: 6279593. DOI: 10.1007/s00401-018-1920-1. View

Saif N, Hristov H, Akiyoshi K, Niotis K, Ariza I, Malviya N . Sex-Driven Differences in the Effectiveness of Individualized Clinical Management of Alzheimer's Disease Risk. J Prev Alzheimers Dis. 2022; 9(4):731-742. DOI: 10.14283/jpad.2022.44. View

Tukiainen T, Villani A, Yen A, Rivas M, Marshall J, Satija R . Landscape of X chromosome inactivation across human tissues. Nature. 2017; 550(7675):244-248. PMC: 5685192. DOI: 10.1038/nature24265. View

Vogt N, Kerby R, Dill-McFarland K, Harding S, Merluzzi A, Johnson S . Gut microbiome alterations in Alzheimer's disease. Sci Rep. 2017; 7(1):13537. PMC: 5648830. DOI: 10.1038/s41598-017-13601-y. View

Bellenguez C, Kucukali F, Jansen I, Kleineidam L, Moreno-Grau S, Amin N . New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022; 54(4):412-436. PMC: 9005347. DOI: 10.1038/s41588-022-01024-z. View

McCarthy M, Raval A . The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease. J Neuroinflammation. 2020; 17(1):317. PMC: 7585188. DOI: 10.1186/s12974-020-01998-9. View

van Dyck C, Sabbagh M, Cohen S . Lecanemab in Early Alzheimer's Disease. Reply. N Engl J Med. 2023; 388(17):1631-1632. DOI: 10.1056/NEJMc2301380. View

Nelson H, Humphrey L, Nygren P, Teutsch S, Allan J . Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002; 288(7):872-81. DOI: 10.1001/jama.288.7.872. View

Toro C, Zhang L, Cao J, Cai D . Sex differences in Alzheimer's disease: Understanding the molecular impact. Brain Res. 2019; 1719:194-207. PMC: 6750802. DOI: 10.1016/j.brainres.2019.05.031. View

10.

Ferretti M, Iulita M, Cavedo E, Chiesa P, Dimech A, Chadha A . Sex differences in Alzheimer disease - the gateway to precision medicine. Nat Rev Neurol. 2018; 14(8):457-469. DOI: 10.1038/s41582-018-0032-9. View

11.

Wiacek M, Hagner W, Zubrzycki I . Measures of menopause driven differences in levels of blood lipids, follicle-stimulating hormone, and luteinizing hormone in women aged 35 to 60 years: National Health and Nutrition Examination Survey III and National Health and Nutrition.... Menopause. 2010; 18(1):60-6. DOI: 10.1097/gme.0b013e3181e7060b. View

12.

Mifflin M, Winslow W, Surendra L, Tallino S, Vural A, Velazquez R . Sex differences in the IntelliCage and the Morris water maze in the APP/PS1 mouse model of amyloidosis. Neurobiol Aging. 2021; 101:130-140. PMC: 8122060. DOI: 10.1016/j.neurobiolaging.2021.01.018. View

13.

Yanguas-Casas N, Crespo-Castrillo A, de Ceballos M, Chowen J, Azcoitia I, Arevalo M . Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid. Glia. 2017; 66(3):522-537. DOI: 10.1002/glia.23263. View

14.

Pinho-Gomes A, Gong J, Harris K, Woodward M, Carcel C . Dementia clinical trials over the past decade: are women fairly represented?. BMJ Neurol Open. 2022; 4(2):e000261. PMC: 9445798. DOI: 10.1136/bmjno-2021-000261. View

15.

Trojano M, Lucchese G, Graziano G, Taylor B, Simpson Jr S, Lepore V . Geographical variations in sex ratio trends over time in multiple sclerosis. PLoS One. 2012; 7(10):e48078. PMC: 3485003. DOI: 10.1371/journal.pone.0048078. View

16.

Kang H, Kawasawa Y, Cheng F, Zhu Y, Xu X, Li M . Spatio-temporal transcriptome of the human brain. Nature. 2011; 478(7370):483-9. PMC: 3566780. DOI: 10.1038/nature10523. View

17.

Coughlan G, Betthauser T, Boyle R, Koscik R, Klinger H, Chibnik L . Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography. JAMA Neurol. 2023; 80(5):462-473. PMC: 10071399. DOI: 10.1001/jamaneurol.2023.0455. View

18.

Shang D, Wang L, Klionsky D, Cheng H, Zhou R . Sex differences in autophagy-mediated diseases: toward precision medicine. Autophagy. 2020; 17(5):1065-1076. PMC: 8143224. DOI: 10.1080/15548627.2020.1752511. View

19.

Mohammad I, Starskaia I, Nagy T, Guo J, Yatkin E, Vaananen K . Estrogen receptor α contributes to T cell-mediated autoimmune inflammation by promoting T cell activation and proliferation. Sci Signal. 2018; 11(526). DOI: 10.1126/scisignal.aap9415. View

20.

Han J, Fan Y, Zhou K, Blomgren K, Harris R . Uncovering sex differences of rodent microglia. J Neuroinflammation. 2021; 18(1):74. PMC: 7972194. DOI: 10.1186/s12974-021-02124-z. View