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An in-depth study into Alzheimer’s has revealed new potential subtypes with unique molecular pathways and opportunities for specific drug targets.
Alzheimer’s disease is the most common form of dementia in the elderly, estimated to affect more than 5.8 million individuals in the U.S., and more than 50 million worldwide (Neff et al. 2021). The hallmark characteristic includes significant and progressive neurological decline, which accounts for disorganization of thought, memory loss, and mood or personality changes.
Neff et al. have been able to characterize Alzheimer’s in a way that helps to create disease subtypes. It is typically considered as a heterogenous disease, meaning having multiple causes and complex networks. While focusing in on the bases of Alzheimer’s, the researchers identified five specific subtypes of the disease (A, B1, B2, C1, and C2). Each subtype has a specific set of genes expressed, as well as different genes and molecular pathways either up-regulated (activated) or down-regulated (de-activated or turned off).
Subtypes were shown to differ strongly in neuronal activity and immune system activity (for example, high expression levels in subtypes B2, C1, C2). The researchers found that disease progression was directly correlated with either one of these increased activities, showing that identification and characterization of the subtypes can be a predictor into future prognosis. In addition, certain molecular pathways and markers are subtype-specific, suggesting greater insight into disease pathogenesis (development of the disease) alongside other enriched pathways. For example, some proteins involved in targeting other molecules for destruction may be up-regulated more in class A, implying a poorer prognosis than other subtypes with different pathways.
While looking at gene expression of certain cell types, the researchers found that each subtype classification had “significant and unique changes in the cell type composition” (Neff, et al. 2021). For example, subtype class C had a specific number of cell types that involves a substantial loss of neurons as compared to other class types. This shows us that the classification can be incredibly important to thinking about how to possibly target and treat Alzheimer’s in different patients.
The researchers then decided to look at the PRS, or potential risk score, of developing Alzheimer’s. They took many examples of genomic data and studied the controls against their own data of the disease with groups A-C. They found that subtypes between classes, such as B1 and B2 or C1 and C2, were very similar, but overall subtypes A, B, and C had significant differences. They found no increased risk of developing Alzheimer’s between the subtype classes, demonstrating that genetic factors were key in predisposition, and not environmental reasons. This test served as a way to affirm that only genetics were behind the class differences, and so precision medicine of these differences is the next step of treatment.
While thinking about medicine, one problem that has plagued researchers for the last several years is about clinical trials of treatments in mice versus in humans. While a treatment may look incredibly promising in mice, it often does not carry over to human clinical trials to the same effect. This study found that while each mouse model may match one specific subtype of Alzheimer’s, it will not match all of them simultaneously, which may partially explain how promising efficacy in an early mouse trial do not align with human trials (assuming all participants had many different subtypes).
Though these results are incredibly promising and help us narrow in on the biological basis of a common disease, there is still a long way to go. These subtypes are not conclusive on the correlation between age and disease severity, which could have been a helpful molecular marker for prognosis. Additionally, the researchers suggest future work in studying each gene expressed per subtype to better understand their roles and heterogeneic functions. There are still a large amount of genes turned on and off in each subtype, and their functions may have an important role still unknown to us.
Many subtype-specific genes have opposite molecular pathways than others (i.e. down vs up-regulated), suggesting that current Alzheimer’s drugs may reduce symptoms in one subtype while exacerbating symptoms in another. One large area of new potential research therefore lies in drug development and biopharmaceuticals. Overall, any new study to improve our knowledge and promote methods for early diagnoses as preventative measures continue to be sought after and useful (Jellinger, K.A. 2021).
There is lots of possible research to keep science looking forward, especially considering the potential impact this may have on pharmaceuticals and drug advancement.
Sophie Byers is a Biology major at Davidson College in Davidson, NC. Contact her at sobyers@davidson.edu.
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References:
Neff, Ryan A., M. Wang, S. Vatansever, L. Guo, C. Ming et al. “Molecular Subtyping of Alzheimer’s Disease Using RNA Sequencing Data Reveals Novel Mechanisms and Targets.” Science Advances, American Association for the Advancement of Science, 1 Jan. 2021, advances.sciencemag.org/content/7/2/eabb5398.
Jellinger K, A: Pathobiological Subtypes of Alzheimer Disease. Dement Geriatr Cogn Disord 2020;49:321-333. doi: 10.1159/000508625
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