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ORIGINAL RESEARCH ARTICLE

Chasing shadows: Investigating X chromosome mediation in late-onset Alzheimer’s disease

Carmel Armon1,2* ,  Lisa A. Cannon-Albright3 ,  Kristina Allen-Brady3 ,  Sharon Wolfson2
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1 Department of Neurology, Loma Linda University School of Medicine, Loma Linda, California, United States of America
2 Department of Neurology, Tel Aviv University School of Medicine and Shamir (Assaf Harofeh) Medical Center, Zerifin, Israel
3 Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Advanced Neurology 2024, 3(2), 3122 https://doi.org/10.36922/an.3122
Submitted: 8 March 2024 | Accepted: 24 May 2024 | Published: 14 June 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Alzheimer’s disease (AD) is a major cause of dementia. While maternal inheritance has been recognized for late-onset AD (LOAD), risk factors have not been identified consistently on the X chromosome. We recently developed a new method to identify an apparent risk of 70% mediated by the X chromosome in newly-presenting cognitive disorders clinic patients with amnestic mild cognitive impairment (aMCI) or early LOAD with unilateral parental lineage for AD or dementia. We sought to confirm our preliminary findings in the Utah Population Database (UPDB). We obtained previously published aggregate data on the risk of AD in the UPDB based on family history, stratified the data by the sex of the proband, and analyzed them using the new method. The X chromosome-attributable relative risk was estimated by calculating the following: Odds ratio (OR) = (women with paternal lineage: Women with maternal lineage)/(men with paternal lineage: Men with maternal lineage). The proportion of genetic risk attributable to the X chromosome is equal to (OR-1)/OR. The analysis did not reveal any risk mediated by the X chromosome, and the null result could be attributed to methodological limitations. Factors that impact the initial or early presentation (incidence) of LOAD, which are appropriate for consideration as risk factors, may not be detectable in a (prevalent) population of deceased individuals. Thus, epidemiological evidence for the contribution of the X chromosome to the development of LOAD will need to be sought prospectively in incident patient populations with newly diagnosed, biologically-confirmed aMCI or LOAD.

Graphical abstract
Keywords
Utah Population Database
Late-onset Alzheimer’s disease
Maternal inheritance
Paternal inheritance
X chromosome
Risk factors
Funding
This research was funded by the National Institute of Health National Institute on Aging 1 (RF1 AG054052-01). Partial support for all data sets within the UPDB was provided by the Huntsman Cancer Institute, Huntsman Cancer Foundation, the University of Utah, and the Huntsman Cancer Institute’s Cancer Center Support Grant (P30 CA42014) from the National Cancer Institute. L.A.C.-A. received support from the Huntsman Cancer Foundation and George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah.
Conflict of interest
The authors declare no conflicts of interest.
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Advanced Neurology, Electronic ISSN: 2810-9619 Print ISSN: 3060-8589, Published by AccScience Publishing
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