International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 355-368 http://medscipublisher.com/index.php/ijmms 358 tau-related neurodegeneration (Kunkle et al., 2019). The interaction between Aβ and tau is significant, as Aβ accumulation can aggravate tau pathology, creating a cycle that accelerates neuronal damage (Ashrafian et al., 2020; Kloske and Wilcock, 2020). Figure 1 Risk of Alzheimer’s disease (A) and dementia (B) by age, APOEgenotypes, and tertiles of the genetic risk score (Adopted from Lee et al., 2018) Image caption: The curves in the figure show that APOE ε4 homozygotes in the high-risk GRS group have the fastest cumulative risk increase, reaching the same risk thresholds significantly earlier than other combinations. In contrast, APOE ε2 carriers in the low-risk GRS group have the slowest cumulative risk increase, with the latest onset age. The results indicate how the interaction between APOE genotypes and GRS leads to age differences in disease risk, further validating the importance of these genetic markers in early disease prediction (Adapted from Lee et al., 2018) 4.3 Neuroinflammation Neuroinflammation is a prominent feature of AD, driven in part by genetic factors. The APOE ε4 allele, a major genetic risk factor for AD, is associated with heightened neuroinflammation (Wolfe et al., 2018; Kloske and Wilcock, 2020). It influences the brain's immune response by promoting the activation of microglia and astrocytes, which can worsen neuronal injury (Figure 2) (Hansen et al., 2018; Wolfe et al., 2018). Additionally, genetic variants in TREM2, a microglial receptor, are linked to AD; TREM2 mutations impair microglial function, limiting Aβ clearance and increasing inflammation and neurodegeneration. 4.4 Synaptic dysfunction Synaptic dysfunction, an early event in AD pathogenesis, is also influenced by genetic factors. The APOE ε4 allele is associated with synaptic loss and dysfunction, contributing to cognitive decline (Wolfe et al., 2018; Kloske and Wilcock, 2020). Other genetic loci implicated in synaptic plasticity and neurotransmission, particularly those affecting lipid metabolism and focal adhesion pathways, have been identified (Dourlen et al., 2019; Kunkle et al., 2019). These genetic variants disrupt synaptic function, impairing neuronal communication and contributing to the cognitive deficits observed in AD (Dourlen et al., 2019; Torres et al., 2021). The genetic landscape of AD significantly influences key pathogenic processes, including amyloid plaque formation, tau pathology, neuroinflammation, and synaptic dysfunction. Understanding these genetic contributions is essential for developing targeted therapeutic strategies and interventions for AD and related dementias. 5 Case Studies 5.1 Genetic links in Lewy body dementia LBD is a complex neurodegenerative disorder characterized by substantial genetic heterogeneity. Recent GWAS identified several genetic risk factors linked to LBD, pinpointing five gene regions significantly associated with disease risk, including APOE, SNCA, and GBA, which have also been implicated in AD and PD (Guerreiro et al., 2018). Additionally, a novel candidate gene, CNTN1, has been proposed, although further validation is necessary (Guerreiro et al., 2018; Chia et al., 2021). The genetic component is estimated to account for approximately 36%
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