Alzheimer’s disease is defined as a progressive neurodegenerative disorder that affects millions of individuals worldwide. This disease, which particularly emerges in older age, is characterized by memory loss, cognitive decline, and the loss of daily living skills. The most common form of the disease is known as sporadic Alzheimer’s, which can sometimes occur at an earlier age due to the influence of genetic factors. This form, called autosomal dominant Alzheimer’s disease (ADAD), is associated with mutations found in the PSEN1 and PSEN2 genes. A recent study presents significant findings regarding the effects of genetic variations in Alzheimer’s disease on the age of onset and the rate of progression of the disease.
The study conducted by Schultz and his colleagues aims to thoroughly examine the effects of the genetic background of Alzheimer’s disease on the clinical progression of the disease. Researchers are analyzing the effects of variants observed in the PSEN1 (Presenilin 1) gene on the age of onset and progression rate of the disease. The fundamental purpose of the study is to understand why Alzheimer’s disease progresses at different rates among individuals by analyzing the effects of these genetic variants on gamma-secretase enzyme and amyloid beta protein production.
This study investigated people with pathogenic mutations in the PSEN1 gene and involved 190 participants from America, Europe, Asia, and Oceania. Research on how PSEN1 polymorphisms affect gamma-secretase activity has revealed that those with low levels of the enzyme exhibit Alzheimer’s symptoms earlier in life and experience a faster rate of disease progression. These results provide more insight into the connection between genetic variants and illness progression through the use of brain imaging and biomarker analysis.
In addition to clinical data, laboratory tests were also used in the study. In order to identify pathogenic genetic variations in the participants’ PSEN1 gene, genetic testing has been performed. Models of genetically engineered cells have been employed to study the impact of gamma-secretase activity on PSEN1 variations. The PSEN1 and PSEN2 genes were knocked out in these mice in order to examine gamma-secretase activity and the formation of amyloid beta. Cerebrospinal fluid (CSF) analysis and brain imaging (PET) have also been utilized for monitoring the development of the disease and the formation of amyloid plaque.
The results of the study indicate that different PSEN1 genetic variants affect gamma-secretase activity in distinct ways. It has been revealed that those with a low gamma-secretase activity have increased production of amyloid beta and that these people experience early onset Alzheimer’s disease symptoms. These people have shown a quicker decline in cognitive skills and a faster reduction in hippocampus volume in PET and CSF investigations. These findings clarify why hereditary factors might cause Alzheimer’s disease to follow distinct clinical courses and why the disease advances at varying rates in different people.
In conclusion, it emphasizes how significant genetic diversity in Alzheimer’s disease is in determining the progression of the disease. It is suggested that PSEN1 variants may play an important role in the development of personalized treatment approaches by affecting the age of onset and progression rate of the disease. These findings may allow for the personalized application of drugs targeting gamma-secretase in the treatment of Alzheimer’s in the future. The study serves as a valuable guide for future treatment strategies by contributing to a better understanding of the genetic foundations of Alzheimer’s disease.
Translated by Nida Dereli
Editor: Elif Duymaz
Reference: Schultz, S. A., Liu, L., Schultz, A. P., Fitzpatrick, C. D., Levin, R., Bellier, J., Shirzadi, Z., Joseph-Mathurin, N., Chen, C. D., Benzinger, T. L. S., Day, G. S., Farlow, M. R., Gordon, B. A., Hassenstab, J. J., Jack, C. R., Jucker, M., Karch, C. M., Lee, J., Levin, J., . . . Chhatwal, J. P. (2024). γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer’s disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). The Lancet Neurology. https://doi.org/10.1016/s1474-4422(24)00236-9
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