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Estimating the X chromosome-mediated risk for developing Alzheimer’s disease

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Abstract

Parental lineage has been shown to increase the risk of Alzheimer’s disease (AD) in the offspring, with greater risk attributed to maternal lineage. While 40 genes/loci have been linked to the risk of developing AD, none has been found on the X chromosome. We propose a new method to estimate the risk for developing AD mediated by the X chromosome in a subgroup of late-onset AD (LOAD) patients with amnestic mild cognitive impairment (aMCI) or early AD and unilateral ancestral history of AD or dementia, and pilot-test it on our clinic data. Records of patients aged 55–80 years presenting to our Memory Disorders Clinic with aMCI or early AD between May 2015 and September 2020, were reviewed, counting patients with a family history of AD or dementia and unilateral ancestral lineage. 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 borne by the X chromosome is equal to (OR-1)/OR. 40 women aged 66.1 ± 5.1 years (mean ± standard deviation) and 31 men aged 68.1 ± 6.5 were identified. The OR was (18:22)/(6:25) = 3.4 (95% confidence interval 1.1–10.1; p = 0.027). The estimated proportion of genetic risk borne by the X chromosome in this population is 70% (95% CI 12–90%). This paper presents the first application of a new method. The numbers are small, the confidence intervals wide. The findings need to be replicated. The method may be generalizable to other diseases.

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Anonymized data can be made available to qualified investigators upon submission of a research protocol and receipt of Shamir (Assaf Harofeh) Medical Center IRB approval.

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Acknowledgements

An abstract describing this work has been presented at the virtual conference of the European Society of Human Genetics (August 28th 2021) and at the American Neurological Association’s 2021 Virtual Annual Meeting (October 16–18th 2021).

Funding

No funding was received for the performance of this study.

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Authors and Affiliations

  1. Department of Neurology, Tel Aviv University School of Medicine and Shamir (Assaf Harofeh) Medical Center, PO Beer Yaakov, 70300, Zerifin, Israel

    Carmel Armon, Sharon Wolfson, Rivka Margalit, Liraz Avraham, Yael Bugen, Amir Cohen, Adi Meiri & Ran Shorer

Authors
  1. Carmel Armon
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  2. Sharon Wolfson
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  3. Rivka Margalit
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  4. Liraz Avraham
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  5. Yael Bugen
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  6. Amir Cohen
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  7. Adi Meiri
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  8. Ran Shorer
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Contributions

All authors contributed to the manuscript through one or more of the following: study conceptualization and design; data acquisition; data analysis; editorial review of manuscript. All authors approve the version to be published.

Corresponding author

Correspondence to Carmel Armon.

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Conflicts of interest

The authors have no potential conflict of interest with regards to this paper.

Ethics approval

The study was approved by the Shamir (Assaf Harofeh) Medical Center Institutional Review Board.

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This retrospective study, based on review of existing medical records, was granted a waiver of consent by the Shamir (Assaf Harofeh) Medical Center IRB.

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Armon, C., Wolfson, S., Margalit, R. et al. Estimating the X chromosome-mediated risk for developing Alzheimer’s disease. J Neurol 269, 2479–2485 (2022). https://doi.org/10.1007/s00415-021-10826-w

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  • DOI: https://doi.org/10.1007/s00415-021-10826-w

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