International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 252-263 http://medscipublisher.com/index.php/ijmms 253 2 Genetic Underpinnings of Alzheimer's Disease 2.1 Key genetic mutations in AD Alzheimer's disease (AD) has been extensively studied in the context of genetic predispositions, particularly with mutations in the APP(Amyloid Precursor Protein), PSEN1 (Presenilin 1), and PSEN2 (Presenilin 2) genes. These mutations are most commonly associated with early-onset familial Alzheimer's disease (EOAD), which follows an autosomal dominant inheritance pattern. APP mutations were among the first to be identified and are known to influence the production of amyloid-beta (Aβ), a peptide that aggregates to form the plaques characteristic of AD. Mutations in PSEN1 are the most common cause of EOAD, accounting for the majority of cases, and are often associated with a more aggressive disease course (Gao et al., 2019). Meanwhile, PSEN2 mutations are rarer and typically result in a later onset compared to PSEN1 mutations, although they still contribute to familial AD (Guven et al., 2021). The APOE (Apolipoprotein E) gene, particularly the ε4 allele, plays a significant role in sporadic forms of AD, which are more common than familial cases. The presence of the APOE ε4 allele is associated with an increased risk of developing late-onset AD (LOAD) and is considered the strongest genetic risk factor for this form of the disease. Interestingly, in the context of autosomal dominant AD, the APOE ε4 allele also influences disease onset and severity, particularly in those carrying APP and PSEN1 mutations, highlighting the complex interplay between these genetic factors (Almkvist and Graff, 2021). 2.2 Pathophysiology and genetic influence The mutations in APP, PSEN1, and PSEN2 genes primarily influence the production and processing of amyloid-beta, leading to its accumulation in the brain, a hallmark of AD. APP mutations typically increase the production of the amyloidogenic Aβ42 peptide, which is prone to aggregation. Mutations in PSEN1 and PSEN2 are known to affect the gamma-secretase complex, which plays a crucial role in the cleavage of APP to produce Aβ42. This dysregulation leads to an increased ratio of Aβ42 to Aβ40, further promoting plaque formation and neurodegeneration (Figure 1) (Costa-Laparra et al., 2023). Figure 1 The physiological structure of the brain and neurons in (a) healthy brain and (b) Alzheimer’s disease (AD) brain (Adopted from Breijyeh and Karaman, 2020) Genetic heterogeneity in AD has significant implications for treatment strategies. The variability in mutations, even within the same gene, can lead to differences in disease onset, progression, and response to treatment. For instance, different PSEN1 mutations can result in varying clinical phenotypes, which necessitates personalized approaches to therapy (Shim et al., 2022). Understanding these genetic differences is critical in developing targeted interventions that can more effectively address the specific pathogenic mechanisms at play in each individual.
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