International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 355-368 http://medscipublisher.com/index.php/ijmms 357 3 Genetic Factors in Dementia 3.1 Common genetic variants The APOE ε4 allele is the most prominent genetic risk factor for AD, with studies demonstrating an increased risk and earlier onset in carriers (Saddiki et al., 2020). The Rotterdam Study, a large cohort analysis, found that APOE ε4 significantly influences both the likelihood and age of onset for AD and dementia, with homozygous carriers facing a particularly elevated risk and earlier onset (Lee et al., 2018). Beyond APOE, other genetic variants such as TREM2 and CLU have also been linked to AD. TREM2 variants, in particular, have been identified in cases of EOAD, indicating their involvement in disease pathogenesis. An analysis of dementia-related gene variants in patients with EOAD who do not carry APOE ε4 found TREM2 variants, suggesting a potential role in increasing AD risk (Park et al., 2020). 3.2 Rare genetic mutations Familial Alzheimer’s disease (FAD) is frequently associated with rare, highly penetrant mutations in the PSEN1, PSEN2, and APP genes, which usually lead to early-onset disease (Jiang et al., 2019). Research involving patients with EOAD has identified several likely pathogenic variants (LPVs) in PSEN1, highlighting its significant role in familial AD (Park et al., 2020). FTD exhibits a strong genetic basis, with research suggesting a high degree of heritability, as around 30% of cases involve a significant family history. Key genetic contributors include autosomal dominant mutations in the C9orf72, GRN, and MAPT genes (Greaves and Rohrer, 2019). These mutations lead to the pathological accumulation of tau protein or progranulin, driving the neurodegenerative processes characteristic of FTD (Panza et al., 2020). 3.3 Polygenic risk scores Polygenic risk scores (PRS) have been developed to assess the cumulative impact of multiple genetic variants on AD risk, integrating numerous single nucleotide polymorphisms (SNPs) associated with the condition. Although the APOE ε4 allele remains the most potent individual predictor, PRS can enhance the precision of AD risk prediction beyond APOE ε4 alone (Lee et al., 2018; Pyun et al., 2021). The interaction between APOE and a PRS comprising 23 AD-associated genetic variants significantly affects the age of onset, with those in the highest risk category (homozygous for APOE ε4 in the top PRS tertile) potentially experiencing onset up to a decade earlier than individuals in the lowest risk group (Figure 1) (Lee et al., 2018). A comprehensive evaluation of genetic risk scores for AD confirmed that PRS is strongly correlated with disease risk, improving the identification of individuals at elevated genetic risk (Stocker et al., 2018). 4 Mechanisms of Genetic Influence on Dementia 4.1 Amyloid plaque formation Amyloid plaques, predominantly composed of amyloid-beta (Aβ) peptides, are a hallmark of AD, with genetic factors playing a pivotal role in their formation and accumulation. Mutations in the amyloid precursor protein (APP) gene and presenilin genes (PSEN1 and PSEN2) elevate Aβ production, leading to early-onset familial AD (Dourlen et al., 2019; Kunkle et al., 2019). Genome-wide association studies (GWAS) have also identified loci linked to late-onset AD (LOAD) that influence APP metabolism and Aβ processing, including ADAM10 and ACE (Kunkle et al., 2019). These genetic variants contribute to the dysregulation of Aβ synthesis, degradation, and aggregation, thereby promoting amyloid plaque development (Dourlen et al., 2019; Gallardo and Holtzman, 2019). 4.2 Tau protein pathology Tau protein pathology, characterized by the presence of NFTs, represents another key aspect of AD. Genetic influences on tau pathology include MAPT gene mutations, which encode the tau protein and can lead to abnormal tau phosphorylation and aggregation (Gallardo and Holtzman, 2019; Guo et al., 2020). Additionally, GWAS have identified risk loci affecting tau-binding proteins, suggesting a genetic predisposition toward
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