International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 355-368 http://medscipublisher.com/index.php/ijmms 356 to enhance diagnostic accuracy, refine risk assessment, and provide a foundation for personalized treatment strategies. A comprehensive understanding of the genetic landscape of dementia is essential for improving management and care, addressing the growing global health challenge posed by this condition. 2 Overview of Dementia Types Dementia encompasses a spectrum of neurodegenerative disorders marked by progressive cognitive decline and memory loss. The major forms include AD, Vascular Dementia (VaD), Lewy Body Dementia (LBD), Frontotemporal Dementia (FTD), and Mixed Dementia, each exhibiting distinct pathological and genetic characteristics that shape their clinical manifestations. 2.1 Alzheimer’s disease AD is the most common type, particularly prevalent among the elderly, characterized by the buildup of amyloid-beta plaques and neurofibrillary tangles (NFTs) in the brain. Genetic factors significantly influence AD risk, with mutations in APP, PSEN1, and PSEN2 linked to familial forms, while the APOE ε4 allele is a prominent risk factor for late-onset AD (Fenoglio et al., 2018; Wang et al., 2019; Ramos et al., 2020). Epigenetic mechanisms, such as DNA methylation and regulatory roles of non-coding RNAs, also contribute to AD pathogenesis (Fenoglio et al., 2018). 2.2 Vascular dementia VaD arises from cerebrovascular pathology that disrupts cerebral blood flow, leading to cognitive deterioration. Genetic determinants associated with cholesterol metabolism, blood pressure regulation, and vascular health increase the risk of VaD. For example, both the APOE ε4 allele and CETP I405V polymorphism have been associated with heightened VaD susceptibility (Maletta et al., 2018). The genetic overlap with other dementias, particularly AD, illustrates the intricate interaction between genetic predisposition and environmental influences (Maletta et al., 2018; Guerreiro et al., 2020). 2.3 Lewy body dementia LBD is distinguished by the accumulation of Lewy bodies, aggregates of alpha-synuclein protein, within the brain. LBD shares clinical and pathological traits with both AD and Parkinson’s Disease (PD), complicating diagnostic differentiation. Genetic studies have identified risk loci such as SNCA, GBA, and APOE, which are associated with LBD susceptibility (Guerreiro et al., 2018; Orme et al., 2020; Noori et al., 2021). The genetic commonalities between LBD and other neurodegenerative diseases suggest shared molecular pathways (Guerreiro et al., 2018; Orme et al., 2020). 2.4 Frontotemporal dementia FTD primarily affects the frontal and temporal brain regions, resulting in personality, behavioral, and language disturbances. Mutations in genes such as GRN, MAPT, and C9orf72 are frequently implicated, contributing to the disorder’s heterogeneity by leading to diverse proteinopathies and clinical phenotypes (Ciani et al., 2019; Wang et al., 2019; Guerreiro et al., 2020; Kwok et al., 2020). The genetic overlap with AD and LBD points to common pathogenic mechanisms across these conditions (Fenoglio et al., 2018; Ciani et al., 2019). 2.5 Mixed dementia Mixed Dementia involves the concurrent manifestation of multiple dementia types, most frequently a combination of AD and VaD. The coexistence of amyloid plaques and vascular lesions in the brain adds complexity to its clinical presentation and diagnostic challenges. Shared genetic risk factors, such as the APOE ε4 allele, contribute to the pathogenesis of mixed dementia, influencing the development of both AD and VaD (Maletta et al., 2018; Wang et al., 2019). Elucidating the genetic and pathological interactions in mixed dementia is essential for advancing targeted therapeutic approaches. The genetic architecture of various dementia forms underscores the disorders' inherent complexity and heterogeneity. Ongoing research into the genetic and molecular mechanisms driving dementia remains critical for refining diagnostic accuracy and enhancing treatment and prevention strategies.
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