International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 355-368 http://medscipublisher.com/index.php/ijmms 355 Research Insight Open Access The Role of Genetic Factors in Dementia LinMou1, LeiWu2, Xinyu Fu2, BoWang2, XuWang2, Xingjun Xiao2 1 Department of Neurology, Harbin First Hospital, Harbin, 150000, Heilongjiang, China 2 Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, Heilongjiang, China Corresponding author: xxiao@hrbmu.edu.cn International Journal of Molecular Medical Science, 2024, Vol.14, No.6 doi: 10.5376/ijmms.2024.14.0035 Received: 10 Oct., 2024 Accepted: 21 Nov., 2024 Published: 05 Dec., 2024 Copyright © 2024 Mou et al., This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Mou L., Wu L., Fu X.Y., Wang B., Wang X., and Xiao X.J., 2024, The role of genetic factors in dementia, International Journal of Molecular Medical Science, 14(6): 355-368 (doi: 10.5376/ijmms.2024.14.0035) Abstract Genetic factors are integral to the pathogenesis of various dementias, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). This study systematically examines the genetic underpinnings of these conditions, emphasizing key gene mutations and their roles in disease progression. The APOE ε4 allele is the predominant genetic risk factor for late-onset AD, significantly affecting both age of onset and overall susceptibility. Moreover, mutations in genes such as TREM2, MAPT, and GRN are strongly linked to FTD and LBD, underscoring the disorders' heterogeneity and complexity. Genome-wide association studies (GWAS) have advanced the identification of risk loci, uncovering novel genetic regions associated with pathways related to amyloid precursor protein (APP) metabolism, Tau protein interactions, immune response, and lipid metabolism. These insights open new avenues for the development of targeted therapies and personalized medical approaches. A comprehensive understanding of genetic factors not only enhances early diagnostic accuracy and risk prediction in dementia but also informs the design of more effective therapeutic strategies. Keywords Dementia; Genetic factors; Alzheimer's disease (AD); Lewy body dementia (LBD); Genome-wide association studies (GWAS); APOE ε4; Risk loci 1 Introduction Dementia encompasses a range of conditions characterized by the progressive deterioration of cognitive abilities, affecting millions globally. With an estimated 47 million individuals currently living with dementia, this figure is expected to double every 20 years, presenting a substantial public health challenge (Reitz et al., 2011; Bottero and Potashkin, 2019). Alzheimer's disease (AD) is the most prevalent form, characterized by memory impairment, cognitive decline, and increased dependency on caregivers (Reitz et al., 2011). Other types, such as frontotemporal dementia and Lewy body dementia, also significantly contribute to the global burden (Delgado-Morales and Esteller, 2017; Hinz and Geschwind, 2017). Research into the genetic aspects of dementia has evolved considerably, with early investigations identifying familial patterns and specific mutations linked to the disease. For instance, mutations in APP, PSEN1, and PSEN2 genes are associated with early-onset AD (EOAD), while MAPT, GRN, and C9ORF72 mutations are linked to frontotemporal dementia (Loy et al., 2013). Genome-wide association studies (GWAS) have since identified numerous genetic variants contributing to the risk of neurodegenerative disorders, illustrating the complex interplay of multiple genetic factors (Adams et al., 2015). Elucidating the genetic basis of dementia is essential for several reasons. It facilitates the identification of high-risk individuals, enabling early intervention strategies that could delay symptom onset (Fan et al., 2019). Genetic insights also reveal the molecular mechanisms underlying the disease, guiding the development of targeted therapeutic approaches (Hinz and Geschwind, 2017). For example, the APOE ε4 allele is a prominent risk factor for AD, influencing the onset age and the rate of cognitive decline (Fan et al., 2019). Moreover, epigenetic changes, such as DNA methylation, have been implicated in dementia pathogenesis, presenting novel therapeutic opportunities (Delgado-Morales and Esteller, 2017). This study aims to delineate the role of genetic factors in the development and progression of dementia by reviewing recent findings on gene expression alterations, genetic mutations, and epigenetic modifications. It seeks
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