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Advanced Neurology

ORIGINAL RESEARCH ARTICLE
Chasing shadows: Investigating X chromosome

mediation in late-onset Alzheimer’s disease

Carmel Armon * , Lisa A. Cannon-Albright 3 , Kristina Allen-Brady , and
1,2
3
Sharon Wolfson 2
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

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
*Corresponding author: history, stratified the data by the sex of the proband, and analyzed them using the new
Carmel Armon
(carmelarmon@llu.edu) method. The X chromosome-attributable relative risk was estimated by calculating
the following: Odds ratio (OR) = (women with paternal lineage: Women with maternal
Citation: Armon C, Cannon- lineage)/(men with paternal lineage: Men with maternal lineage). The proportion of
Albright LA, Allen-Brady K,
Wolfson S. Chasing shadows: genetic risk attributable to the X chromosome is equal to (OR-1)/OR. The analysis
Investigating X chromosome did not reveal any risk mediated by the X chromosome, and the null result could
mediation in late-onset be attributed to methodological limitations. Factors that impact the initial or early
Alzheimer’s disease. Adv Neuro.
2024;3(2):3122. presentation (incidence) of LOAD, which are appropriate for consideration as risk
doi: 10.36922/an.3122 factors, may not be detectable in a (prevalent) population of deceased individuals.
Received: March 8, 2024 Thus, epidemiological evidence for the contribution of the X chromosome to the
development of LOAD will need to be sought prospectively in incident patient
Accepted: May 24, 2024
populations with newly diagnosed, biologically-confirmed aMCI or LOAD.
Published Online: June 14, 2024
Copyright: © 2024 Author(s). Keywords: Utah Population Database; Late-onset Alzheimer’s disease; Maternal
This is an Open-Access article
distributed under the terms of the inheritance; Paternal inheritance; X chromosome; Risk factors
Creative Commons Attribution
License, permitting distribution,
and reproduction in any medium,
provided the original work is
properly cited. 1. Introduction
Publisher’s Note: AccScience Alzheimer’s disease (AD) is a major cause of dementia worldwide and imposes a great
Publishing remains neutral with financial and social burden. The incidence of AD is projected to rise, particularly in
regard to jurisdictional claims in
published maps and institutional developed countries, with the aging of the population due to the loss of competing
1
affiliations causes of mortality. AD is characterized pathologically by extracellular accumulation

Volume 3 Issue 2 (2024) 1 doi: 10.36922/an.3122