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Alzheimer's disease (AD) remains one of the most prevalent neurodegenerative disorders affecting millions of people worldwide. Despite significant research efforts, the genetic basis of AD is still not fully understood. In this study, we aimed to shed light on the genetic underpinnings of AD onset by targeting neuroanatomical, cardiovascular, and cognitive-associated markers in familial AD within the Paisa community, a genetic isolate from Antioquia, Colombia. Through a targeted analysis, we focused on a multigenerational family with a shared genetic background and a high prevalence of the PSEN1 E280A allele, which is fully penetrant and autosomal dominant, leading to early-onset AD.
Understanding the Genetic Complexity of Alzheimer's Disease
Alzheimer's disease is a complex disorder influenced by both genetic and environmental factors. Genome-wide association studies (GWAS) have identified potential candidate genes for sporadic AD with an age of onset above 65 years. However, many of these genes have failed to replicate across different populations due to the heterogeneity of genetic backgrounds and environmental exposures. To overcome this challenge and increase the power of our analysis, we chose to study a well-defined genetic isolate, the Paisa community, which originated from a common ancestor in Northern Spain during the 1500s. This community experiences a high frequency of the PSEN1 E280A allele, making AD quite common and providing an excellent opportunity to study the genetic underpinnings of AD onset.
Research and Discussion
Unraveling the Age of Onset Variability in Familial AD
The age of onset of AD can vary significantly, even among individuals carrying the same fully penetrant mutation. Our main goal was to explore the factors contributing to this variability within the Paisa community. We used 65 genetic markers related to Alzheimer's disease to investigate the wide range of AD onset, which can span from the early 30s to late 70s within this community.
Expanding the Sample Size for More Robust Findings
Before this study, there were two preliminary investigations involving smaller sample sizes, which might have limited the detection of additional relevant genes associated with AD onset. To address this limitation and identify new genes, we expanded the sample size, including more PSEN1 E280A carriers in the study. This enlargement allowed us to detect the protective effect of the APOEE2 allele, which delays the AD age of onset by approximately 8.2 years. Our findings confirmed and reinforced previous reports that the APOEE2 variant plays a protective role in the onset of AD not only in sporadic cases but also in familial cases, such as those carrying the PSEN1 E280A mutation.
Beta Amyloid and Its Controversial Role in AD
Beta amyloid (Aβ) has been a subject of debate in AD research. While some evidence suggests its involvement in the pathogenesis of AD, other studies indicate that its accumulation does not necessarily correlate with dementia onset. Nonetheless, certain genes causative of familial AD, including APP, PSEN1, and PSEN2, are involved in the processing of Aβ peptides. Increased deposition of Aβ-42/43 peptides leads to the formation of amyloid fibrils, which underlie the pathogenic process in familial AD. Studies on the PSEN1 E280A mutation have shown that it specifically increases the production of amyloidogenic peptide Aβ-42, potentially contributing to disease onset.
The Impact of APOE Variants on AD Onset
The APOE gene has been extensively studied in relation to AD risk. Our findings further support the notion that the APOEE2 allele confers protection against AD onset, whereas the APOEE4 variant accelerates it. The protective effect of APOEE2 appears to be related to its ability to improve the clearance of central Aβ, while APOEE4 hinders this clearance, favoring the formation of aggregates and the progression of the disease.
ASTN2 and SNTG1: Potential AD Modifiers
In our study, we identified two genetic variants, rs7852878 within ASTN2 and rs16914781 within SNTG1, that were associated with delayed AD onset in individuals carrying the PSEN1 E280A mutation. ASTN2 is involved in glial-guided neuronal migrations, and its genomic variants have been linked to various neurocognitive and psychiatric disorders. Similarly, SNTG1, an adapter protein exclusively expressed in neurons, has been implicated in schizophrenia and AD pathophysiology. Our research suggests that these genetic variants exert a protective effect by delaying AD onset, especially when the APOE*E2 allele is also present.
Implications for Future Research
Our study provides valuable insights into the genetic complexity of AD onset within the Paisa community. By focusing on a genetic isolate with a shared background, we were able to identify specific genetic variants associated with delayed AD onset. Further research is needed to understand the underlying mechanisms of these interactions and to explore potential therapeutic interventions based on these genetic insights.
Alzheimer's disease remains a challenging and devastating condition affecting millions of individuals worldwide. Our study focused on the genetic underpinnings of AD onset in the Paisa community, providing significant insights into the influence of specific genetic variants on disease progression. The protective effect of the APOE*E2 allele and the potential modifiers ASTN2 and SNTG1 shed new light on the complex interplay of genes involved in AD. As research in this field continues, these findings may pave the way for future treatments and interventions aimed at delaying or preventing AD onset, offering hope to those at risk and their families.
- Alzheimer's Association. (2021). 2021 Alzheimer's disease facts and figures. Alzheimer's & Dementia, 17(3), 327-406.
- Cacace, R., Sleegers, K., & Van Broeckhoven, C. (2016). Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimer's & Dementia, 12(6), 733-748.
- Acosta-Baena, N., Sepulveda-Falla, D., Lopera-Gomez, C. M., Jaramillo-Elorza, M. C., Moreno, S., Aguirre-Acevedo, D. C., ... & Glatzel, M. (2011). Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. The Lancet Neurology, 10(3), 213-220.
- Cruchaga, C., Karch, C. M., Jin, S. C., Benitez, B. A., Cai, Y., Guerreiro, R., ... & Harari, O. (2014). Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature, 505(7484), 550-554.
- Bettens, K., Sleegers, K., & Van Broeckhoven, C. (2010). Genetic insights in Alzheimer's disease. The Lancet Neurology, 9(11), 1107-1115.
- Ramanan, V. K., Kim, S., Holohan, K., Shen, L., Nho, K., Risacher, S. L., ... & Saykin, A. J. (2012). Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks. Brain Imaging and Behavior, 6(4), 634-648.
- Raj, T., & Karch, C. M. (2017). Genetics of Alzheimer disease. In Alzheimer Disease and Frontotemporal Dementia: Methods and Protocols (pp. 489-509). Humana Press.
- Escott-Price, V., Sims, R., Bannister, C., Harold, D., Vronskaya, M., Majounie, E., ... & Morgan, K. (2015). Common polygenic variation enhances risk prediction for Alzheimer's disease. Brain, 138(12), 3673-3684.
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