Precision Medicine: A powerful tool for the treatment of neurodegenerative diseases

By: Alexander Hindeleh

Introduction:

As the population of the United States continues to age, the prevalence of  neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s disease (PD), is steadily increasing (1). These disorders are associated with a progressive loss of neurons, leading to increased neuroinflammation and neural circuitry dysfunction. Over time, neurodegenerative diseases affect motor function, memory, speech, and day-to-day activities. Scientists believe that neurodegenerative disorders are caused by a combination of environmental, genetic, and lifestyle factors (2). Since the cause of these disorders is not fully understood, we must explore personalized approaches for treatment or reduction of symptoms. In this article, I will describe recent advancements in precision medicine that have shown great potential for the treatment and diagnosis of neurodegenerative disease.

Alzheimer’s Disease:

As described by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Alzheimer’s disease is characterized by a decline in learning and memory and at least one other cognitive domain that affects daily functioning (3). This disorder affects 1 in 9 individuals in the United States aged 65 or older; , therefore, appropriate and early diagnoses and treatments are necessary (4). The common pathophysiological hallmarks include abnormal accumulations of amyloid-beta and tau protein plaques. These plaques contribute to microglial dysfunction—the brain’s main immune cells responsible for removing toxic proteins—and disrupt neural circuits by building up around synapses, reducing communication between neurons. Alzheimer’s does not have an exact, defined cause, and is believed to be a result of many possible factors, ranging from mutations in the APOE gene, lifestyle factors like smoking or excessive alcohol consumption, and high cholesterol. 

In a recent clinical trial, researchers at the UCLA David Geffen School of Medicine treated 25 Alzheimer’s disease patients with personalized protocols over a 9-month test period (5). After evaluating potential Alzheimer’s contributors in each patient through genetic, biochemical, and brain scan testing, the researchers developed a strict, detailed protocol for each patient, whether anti-inflammatory herbal supplements for patients with elevated systemic inflammation or vitamin D supplements for patients with inadequate nutrient levels. The results showed an average increase of 0.3% of brain gray matter through magnetic resonance imaging (MRI), contrary to traditional Alzheimer’s pathology, which decreases gray matter. The researchers also observed a significant increase in serum vitamin D levels, an improvement in lipid profile (a lower ratio of triglycerides-to-high-density-lipoproteins). Conversely, they observed a decrease in systemic inflammation and glycation (hemoglobin A1C levels), indicating some recovery from traditional Alzheimer’s symptoms. Overall, this pilot study lays a successful framework for future personalized medicine protocols for diverse Alzheimer’s patient populations. 

Emerging Technologies for Precision Medicine:

Recent advancements in next-generation sequencing have greatly expanded our understanding of the molecular mechanisms underlying neurodegenerative disorders. Single-cell transcriptomics enables researchers to profile gene expression changes within individual cells, attributing specific messenger RNA (mRNA)  upregulations or downregulations to particular brain cell types, like microglia or astrocytes (6). This high-resolution approach offers deeper insight into cell-type–specific pathological processes, providing context that traditional bulk RNA-sequencing methods don’t account for. Recent studies have shown the importance of accounting for cellular heterogeneity when studying neurodegenerative disease, especially in identifying disease-relevant cell states that vary across patients (7).

A newer technique, spatial transcriptomics, was named “Method of the Year” in 2020 by Nature for its major contributions to the study of structure-function relationships in many complex tissues, including the brain (8). One widely used platform, 10x Genomics’ Visium, uses specialized glass slides with spatially barcoded capture areas to measure gene expression throughout brain regions. This method adds spatial context to transcriptional studies and can be integrated with single-cell RNA-seq data to achieve spatial, single-cell–level resolution. Additionally, the emergence of spatial genomic brain atlases will allow scientists to compare their own datasets with reference maps from control or diseased brains to identify region-specific gene expression changes. In the context of PD, for example, the striatum plays a vital role in controlling dopaminergic signaling—typically impaired in PD pathology. Through spatial transcriptomics, researchers can precisely map gene expression changes in the striatum to uncover disrupted signaling pathways and understand how these may cause motor and cognitive deficits. This technology will allow for identification of patient-specific molecular signatures that can guide further personalized treatment strategies and ameliorate clinical outcomes. 

Precision Medicine for Parkinson’s Disease:

Parkinson’s disease is a progressive, neurodegenerative disorder that causes motor deficits, such as tremor, rigidity, and bradykinesia, which is slowness of movement. Scientists believe that PD is caused by a combination of environmental and genetic factors, and is identified by the loss of dopaminergic neurons in the brain region titled substantia nigra pars compacta (9). This loss impacts the “direct pathway” in the basal ganglia, another brain region, which directly projects to motor neurons which are responsible for controlling movement in the body. Another hallmark of PD is an abnormal buildup of alpha-synuclein proteins in the brain, which interrupt normal brain cell functions. Due to the heterogeneity in PD causes and pathology, personalized treatments are needed to properly treat the diverse patient populations affected by this disorder. 

A recent study used spatial transcriptomics to identify T-cell interactions in the substantia nigra, which are increased as a result of dopaminergic neurodegeneration in typical PD pathology (10). They found that PD induced an alteration in the spatial organization of T cells in specific cell types, such as astrocytes and endothelial cells, which was shown through co-integration with single-nucleus RNA sequencing (snRNA-seq). These changes can help scientists and clinicians understand how immune cells are activated in different brain regions and how to use these immune responses to improve outcomes for PD patients. Other emerging studies and clinical trials have shown promising improvements in symptoms following strict, personalized regimens of exercise, diet, and lifestyle. More research is needed, but with spatial transcriptomics becoming more commercially available, I am confident that more biomarkers for PD will become recognized in the scientific community. Then, clinicians and scientists can work on personalized treatments to benefit patients based on their individual needs. 

Conclusion:

Although precision medicine is an emerging discipline, it has already shown great potential for treatments of neurodegenerative diseases. Further studies are needed to evaluate its efficacy, and to establish exact protocols for diverse patient populations based on baseline values for biomarkers of disease. As technologies like single-cell and spatial transcriptomics become more commercially available, they will be essential for further clinical trials. I anticipate a future where personalized medicine will be more integrated in clinics worldwide to improve outcomes for those suffering from neurodegenerative diseases.

Sources

1. Brown, R. C., Lockwood, A. H., & Sonawane, B. R. (2005). Neurodegenerative diseases: An overview of environmental risk factors. Environmental Health Perspectives, 113(9), 1250–1256. https://doi.org/10.1289/ehp.7567

2. Lamptey, R. N. L., Chaulagain, B., Trivedi, R., Gothwal, A., Layek, B., & Singh, J. (2022). A review of the common neurodegenerative disorders: Current therapeutic approaches and the potential role of nanotherapeutics. International Journal of Molecular Sciences, 23(3), 1851. https://doi.org/10.3390/ijms23031851

3. Yokoi, T. (2023). Alzheimer's disease is a disorder of consciousness. Gerontology and Geriatric Medicine, 9, 23337214231159759. https://doi.org/10.1177/23337214231159759

4.  Alzheimer's Association. (2023). 2023 Alzheimer's disease facts and figures. Alzheimer's &     Dementia, 19(4), 1598–1695. https://doi.org/10.1002/alz.13016

5. Hampel, H., Toschi, N., Babiloni, C., Baldacci, F., Black, K. L., Bokde, A. L. W., ... & Vergallo, A. (2022). Precision medicine approach to Alzheimer's disease: Current state and future perspectives. Frontiers in Neuroscience, 16, 816144.

6. Murdock, M. H., & Tsai, L.-H. (2023). Insights into Alzheimer's disease from single-cell genomic approaches. Nature Neuroscience, 26(2), 181–195. https://doi.org/10.1038/s41593-022-01222-2

7. ​​He, Z., Chen, Q., Wang, K., Lin, J., Peng, Y., Zhang, J., Yan, X., & Jie, Y. (2024). Single-cell transcriptomics analysis of cellular heterogeneity and immune mechanisms in neurodegenerative diseases. European Journal of Neuroscience, 59(3), 333–357. https://doi.org/10.1111/ejn.16242

8. Nature Methods. (2021). Method of the Year 2020: spatially resolved transcriptomics. Nature Methods, 18(1), 1. https://doi.org/10.1038/s41592-020-01042-x

9. Balestrino, R., & Schapira, A. H. V. (2020). Parkinson disease. European Journal of Neurology, 27(1), 27–42. https://doi.org/10.1111/ene.14108

10. Jakubiak, K., Paryani, F., Kannan, A., Lee, J., Madden, N., Li, J., Chen, D., Mahajan, A., Xia, S., Flowers, X., Menon, V., Sulzer, D., Goldman, J., Sims, P. A., & Al-Dalahmah, O. (2024). The spatial landscape of glial pathology and T-cell response in neurodegeneration. bioRxiv. https://doi.org/10.1101/2024.01.08.574736

Picture credit: https://knowledge.wharton.upenn.edu/article/precision-medicine-new-paradigms-risks-opportunities/