International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 355-368 http://medscipublisher.com/index.php/ijmms 360 gene encoding glucocerebrosidase, are closely linked to LBD, particularly in patients who do not carry the APOE ε4 allele, indicating different genetic pathways contributing to disease risk (Kaivola et al., 2021). 5.2 Genetic association studies of late-onset Alzheimer's disease (LOAD) LOAD, the most prevalent form of AD, typically manifests after age 65. While variations in the APOE gene are well-established as major genetic risk factors for LOAD, they account for only part of the genetic risk, leaving a significant portion of the heritability unexplained (Kunkle et al., 2019; Ortega-Rojas et al., 2022). A large-scale genome-wide association meta-analysis by Kunkle et al. (2019) identified new risk loci associated with LOAD, confirming 20 previously recognized loci and discovering five novel genome-wide loci: IQCK, ACE, ADAM10, ADAMTS1, and WWOX. These findings underscore the significance of immune response, lipid metabolism, tau protein binding, and APP metabolism in the pathogenesis of LOAD. Comprehensive genotype analysis across multiple cohort samples revealed the importance of both common and rare genetic variants in influencing LOAD risk, suggesting that rare variants may significantly impact disease susceptibility. This discovery provides new avenues for exploring the genetic mechanisms of Alzheimer's disease and highlights potential genetic targets for future therapeutic development. Figure 4 Manhattan plot of meta-analysis of stage 1, 2, and 3 results for genome-wide association with Alzheimer’s disease (Adopted from Kunkle et al., 2019) Image caption: The figure presents the results of a genome-wide association study related to late-onset Alzheimer's disease (LOAD), specifically highlighting significant genetic loci and their performance across different stages of the study. The figure shows the genetic associations of multiple loci across different samples, emphasizing the consistency observed across various datasets, thereby validating the correlation of these loci with LOAD. These findings support the critical roles of immune response, lipid metabolism, Tau protein binding, and APP metabolism in the pathology of LOAD, offering new insights into the genetic basis of Alzheimer's disease and providing crucial clues for potential therapeutic targets (Adapted from Kunkle et al., 2019) 5.3 Comparative analysis of genetic influences in different dementia types The genetic architecture of dementia encompasses distinct and overlapping risk factors across various types. AD is chiefly linked to mutations in APP, PSEN1, and PSEN2, which drive amyloid-beta plaque accumulation (Kwok et al., 2020). In contrast, LBD is associated with mutations in genes such as GBA and SNCA, which facilitate Lewy body formation (Guerreiro et al., 2018; Chia et al., 2021; Kaivola et al., 2021). The APOE ε4 allele serves as a shared genetic risk factor for both AD and LBD, indicating a common pathogenic pathway involving lipid metabolism and amyloid-beta processing (Kaivola et al., 2021; Lee et al., 2021). FTD and VaD display distinct genetic landscapes. FTD often involves mutations in MAPT and GRN, affecting tau protein and progranulin, respectively (Guerreiro et al., 2020), while VaD is linked to mutations in NOTCH3, which play a role in maintaining vascular integrity. Despite these differences, genetic overlap exists among
RkJQdWJsaXNoZXIy MjQ4ODYzNQ==