International Journal of Clinical Case Reports 2024, Vol.14, No.5, 276-289 http://medscipublisher.com/index.php/ijccr 279 This case underscores the importance of a multimodal diagnostic approach, which can significantly enhance the sensitivity and specificity of early AD diagnosis. It also demonstrates the critical role of biomarkers in guiding clinical decisions, particularly in cases where cognitive symptoms alone may not provide sufficient diagnostic clarity. Such integrated approaches are vital for early intervention and for the development of personalized treatment strategies, ultimately improving patient outcomes and quality of life. 4 Genetic Factors and Early Onset Alzheimer's Disease 4.1 Familial Alzheimer's disease and genetic mutations Familial Alzheimer’s Disease (FAD) is a rare hereditary form of Alzheimer's Disease (AD) that usually presents with an early onset, often before the age of 65. It is caused by mutations in specific genes that follow an autosomal dominant inheritance pattern. The three most common genes implicated in FAD are amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). Mutations in these genes lead to abnormal processing of amyloid precursor protein, resulting in excessive production of amyloid-beta peptides, which aggregate to form plaques, a hallmark of AD pathology (Lanoiselée et al., 2017). These genetic mutations are responsible for up to 10% of early-onset AD cases, with PSEN1 mutations being the most common. The clinical presentation and age of onset can vary significantly depending on the specific mutation. For instance, individuals with the PSEN1 mutation often exhibit earlier onset and faster disease progression compared to those with APPor PSEN2 mutations. Recent research provides evidence supporting the role of novel mutations in familial Alzheimer's disease (FAD) in both amyloid-beta production and tau protein accumulation. For example, the APP Osaka mutation has been shown to result in a heavy tau burden with only subtle amyloid-beta accumulation in the brain, challenging the traditional view of amyloid-beta plaques as the primary driver of Alzheimer's pathology (Shimada et al., 2020) . Another study involving a novel AβPP M722K mutation found that this mutation leads to increased secretion of amyloid-beta and enhanced tau phosphorylation, contributing to the pathogenesis of early-onset FAD (Wang et al., 2023). These findings highlight the complex interaction between amyloid-beta and tau in Alzheimer's disease, with some novel mutations influencing both pathways, potentially providing targets for therapeutic intervention. 4.2 Risk genes: APOE-ε4 and other genetic markers The apolipoprotein E (APOE) gene, particularly the ε4 allele, is the most significant genetic risk factor for sporadic and familial Alzheimer's Disease (AD). Individuals who carry one copy of the APOE-ε4 allele have a 3-4 times higher risk of developing AD, while those with two copies have a 10-15 times increased risk. This allele is associated with earlier onset and more rapid progression of the disease. APOE-ε4 influences AD risk through several mechanisms, including impaired amyloid-beta clearance, increased amyloid deposition, and enhanced tau phosphorylation (Di Battista et al., 2016). Recent research has highlighted that the impact of APOE-ε4 on AD risk is modulated by other genetic and environmental factors. For example, variants in genes such as TREM2, which is involved in microglial function, and SORL1, which is related to amyloid processing, have been shown to interact with APOE-ε4, further influencing the risk of AD (Stocker et al., 2018). Moreover, there is increasing evidence that APOE-ε4 may differentially affect brain function even in young, cognitively healthy individuals, suggesting that the allele exerts its influence long before the onset of clinical symptoms. This has implications for early detection and prevention strategies, as individuals carrying APOE-ε4 may benefit from more frequent monitoring and early lifestyle interventions. Additionally, the development of genetic risk scores that incorporate multiple AD-related gene variants alongside APOE-ε4 has shown promise in improving the predictive accuracy for AD risk, particularly in individuals who are APOE-ε4 negative but still at risk due to other genetic factors. 4.3 Case study analysis: genetic testing and family history A detailed case study of a 47-year-old male with a family history of early-onset Alzheimer's Disease (AD) illustrates the importance of genetic testing and family history in early diagnosis and management. The patient presented with mild memory impairment and executive dysfunction, raising concerns given his young age and
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