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Advanced Neurology

ORIGINAL RESEARCH ARTICLE
Ethnogenetic-specific mutations in Alzheimer’s

disease: A marker of clinical outcomes

Georgia Uebergang, Mourad Tayebi, and Utpal K. Adhikari*
Neuroimmunology Laboratory, School of Medicine, Western Sydney University, Campbelltown,
New South Wales, Australia

Abstract

Alzheimer’s disease (AD) presents a substantial global health challenge, with its
pathogenesis influenced by a complex interplay of genetic and molecular factors.
Approximately 1% of AD cases are attributed to early onset autosomal dominant familial
AD (fAD), with genetics contributing to about 70% of overall AD risk. Understanding the
genetic basis and molecular mechanisms is paramount for early diagnosis and prognosis
improvement. This study explores a previously underexplored area of fAD, examining
how different mutations within the same gene, encoding a single protein, may influence
the clinical features and progression of fAD subtypes. Our investigation focuses on distinct
fAD subtypes — Iranian (T714A), Swedish (KM670/671NL), and Australian (L723P) — and
their associated mutations within the C-terminus domain of amyloid precursor protein
(APP). Through an extensive analysis of existing literature encompassing clinical severity,
pathogenicity, neuropathology, and biological processes, we reveal critical insights into
these fAD subtypes. Leveraging bioinformatics tools, we correlate the physicochemical
properties of translated mutant proteins with clinical and neuropathological features.
Notably, our findings demonstrate that mutations occurring between codons 714 and 717
*Corresponding author:
Utpal K. Adhikari of the APP gene share a higher similarity, resulting in lower root mean squared deviation
(U.Adhikari@westernsydney.edu.au) scores. These mutations are associated with a broader spectrum of clinical symptoms,
Citation: Uebergang G, Tayebi M, including myoclonus and seizures, and an earlier age of onset. Moreover, we observe a
Adhikari UK, 2023, Ethnogenetic- direct correlation between the location of genetic mutations on the protein sequence
specific mutations in Alzheimer’s and specific physicochemical properties, clinical presentations, and neuropathological
disease: A marker of clinical
outcomes. Adv Neuro, 2(4): 1734. features among fAD subtypes. Mutations with higher structural similarity tend to
https://doi.org/10.36922/an.1734 manifest similar clinical and physical characteristics. While certain neuropathological
findings correlate with an increasing epitope toxicity burden, our analysis indicates that
Received: August 31, 2023
epitope toxicity does not significantly impact clinical outcomes. In summary, our study
Accepted: November 28, 2023 provides novel insights into the heterogeneous nature of fAD subtypes, illuminating
Published Online: December 15, the intricate relationship between genetic mutations, physicochemical properties, and
2023 clinical manifestations. These findings offer a foundation for further research into tailored
Copyright: © 2023 Author(s). therapeutic approaches and personalized medicine for fAD.
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution Keywords: Alzheimer’s disease; Amyloid precursor protein mutations; Ethnogenetic;
License, permitting distribution, Epitopes; Bioinformatics; Epitope toxicity
and reproduction in any medium,
provided the original work is
properly cited.
Publisher’s Note: AccScience
Publishing remains neutral with 1. Introduction
regard to jurisdictional claims in
published maps and institutional Alzheimer’s disease (AD) represents a major health-care challenge, notably as
affiliations. the predominant cause of dementia in the elderly [1,2] . Despite significant progress

Volume 2 Issue 4 (2023) 1 https://doi.org/10.36922/an.1734