Ethnogenetic-specific mutations in Alzheimer’s disease: A marker of clinical outcomes

Abstract

Alzheimer’s disease (AD) presents a substantial global health challenge, with its pathogenesis influenced by a complex interplay of genetic and molecular factors. Approximately 1% of AD cases are attributed to early onset autosomal dominant familial AD (fAD), with genetics contributing to about 70% of overall AD risk. Understanding the genetic basis and molecular mechanisms is paramount for early diagnosis and prognosis improvement. This study explores a previously underexplored area of fAD, examining how different mutations within the same gene, encoding a single protein, may influence the clinical features and progression of fAD subtypes. Our investigation focuses on distinct fAD subtypes — Iranian (T714A), Swedish (KM670/671NL), and Australian (L723P) — and their associated mutations within the C-terminus domain of amyloid precursor protein (APP). Through an extensive analysis of existing literature encompassing clinical severity, pathogenicity, neuropathology, and biological processes, we reveal critical insights into these fAD subtypes. Leveraging bioinformatics tools, we correlate the physicochemical properties of translated mutant proteins with clinical and neuropathological features. Notably, our findings demonstrate that mutations occurring between codons 714 and 717 of the APP gene share a higher similarity, resulting in lower root mean squared deviation scores. These mutations are associated with a broader spectrum of clinical symptoms, including myoclonus and seizures, and an earlier age of onset. Moreover, we observe a direct correlation between the location of genetic mutations on the protein sequence and specific physicochemical properties, clinical presentations, and neuropathological features among fAD subtypes. Mutations with higher structural similarity tend to manifest similar clinical and physical characteristics. While certain neuropathological findings correlate with an increasing epitope toxicity burden, our analysis indicates that epitope toxicity does not significantly impact clinical outcomes. In summary, our study provides novel insights into the heterogeneous nature of fAD subtypes, illuminating the intricate relationship between genetic mutations, physicochemical properties, and clinical manifestations. These findings offer a foundation for further research into tailored therapeutic approaches and personalized medicine for fAD.