January 08, 2021 -Using data from RNA sequencing, a team from the Icahn School of Medicine at Mount Sinai has detected three molecular subtypes of Alzheimers disease that could advance precision medicine treatments for the condition.
Alzheimers is the most common form of dementia, but it ranges in its biological and pathological manifestations. Researchers noted that there is a growing body of evidence suggesting that disease progression and responses to interventions differ significantly among Alzheimers patients.
While some patients have slow cognitive decline, others decline rapidly; some have significant memory loss and an inability to remember new information while others dont; and some patients experience psychosis or depression associated with Alzheimers while others dont.
Such differences strongly suggest there are subtypes of Alzheimers disease with different biological and molecular factors driving disease progression, said Bin Zhang, PhD, the lead author of the study, Director of the Center for Transformative Disease Modeling, and Professor of Genetics and Genomic Sciences at the Icahn School of Medicine.
RNA is a genetic molecule similar to DNA that encodes the instructions for making proteins. RNA sequencing is a technology that shows the presence and quantity of RNA in a biological sample like a brain slice.
To identify the subtypes of Alzheimers disease, researchers used a computational biology approach to understand the relationships among different types of RNA, clinical and pathological traits, and other biological factors that potentially drive the diseases progress.
The team analyzed RNA sequencing data of more than 1,500 samples across five brain regions from hundreds of deceased patients with Alzheimers disease and normal controls, and were able to identify three major molecular subtypes of Alzheimers disease. These subtypes were independent of age and disease stage, and were replicated across multiple brain regions in two cohort studies.
These subtypes correspond to different combinations of multiple dysregulated biological pathways leading to brain degeneration. Two neuropathological hall marks of Alzheimers disease, tau neurofibrillary tangle and amyloid-beta plaque, are significantly increased only in certain subtypes.
While many recent studies have shown that an elevated immune response may help cause Alzheimers, more than half of Alzheimers brains dont show increased immune response compared to normal, healthy brains. The analysis further revealed subtype-specific molecular drivers in Alzheimers progression in these samples.
The research also identified the correspondence between these molecular subtypes and the existing Alzheimers animal models used for mechanistic studies and for testing candidate therapeutics. This could partly explain why many drugs that succeeded in mouse models failed in human Alzheimers trials, which likely involved participants belonging to different molecular subtypes.
The subtyping described by the researchers was performed post mortem using the patients brain tissue. However, researchers said that if the findings were validated by future studies, the results could lead to the identification of biomarkers and clinical features in living patients associated with these molecular subtypes and earlier diagnosis and intervention.
Our systematic identification and characterization of the robust molecular subtypes of Alzheimers disease reveal many new signaling pathways dysregulated in Alzheimers and pinpoint new targets, said Zhang.
These findings lay down a foundation for determining more effective biomarkers for early prediction of Alzheimers, studying causal mechanisms of Alzheimers, developing next-generation therapeutics for Alzheimers, and designing more effective and targeted clinical trials, ultimately leading to precision medicine for the disease.
Going forward, studies should aim to advance the results found in this research to further achieve precision medicine for Alzheimers.
The remaining challenges for future research include replication of the findings in larger cohorts, validation of subtype specific targets and mechanisms, identification of peripheral biomarkers and clinical features associated with these molecular subtypes, Zhang concluded.
Read the rest here:
Discovery of New Alzheimer's Subtypes May Speed Precision Medicine - HealthITAnalytics.com
Recommendation and review posted by G. Smith
