Discovery of New Alzheimer’s Subtypes May Speed Precision Medicine

Using data from RNA sequencing, a team from the Icahn School of Medicine at Mount Sinai has detected three molecular subtypes of Alzheimer’s disease that could advance precision medicine treatments for the condition.

Alzheimer’s 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 Alzheimer’s 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 don’t; and some patients experience psychosis or depression associated with Alzheimer’s while others don’t.

“Such differences strongly suggest there are subtypes of Alzheimer’s 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 Alzheimer’s 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 disease’s progress.

The team analyzed RNA sequencing data of more than 1,500 samples across five brain regions from hundreds of deceased patients with Alzheimer’s disease and normal controls, and were able to identify three major molecular subtypes of Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s, more than half of Alzheimer’s brains don’t show increased immune response compared to normal, healthy brains. The analysis further revealed subtype-specific molecular drivers in Alzheimer’s progression in these samples.

The research also identified the correspondence between these molecular subtypes and the existing Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s disease reveal many new signaling pathways dysregulated in Alzheimer’s and pinpoint new targets,” said Zhang.

“These findings lay down a foundation for determining more effective biomarkers for early prediction of Alzheimer’s, studying causal mechanisms of Alzheimer’s, developing next-generation therapeutics for Alzheimer’s, 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 Alzheimer’s.

“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.