Three Molecular Subtypes of Alzheimer Disease Identified

Three major molecular subtypes of Alzheimer disease (AD) identified by researchers could be biomarkers that lead to earlier diagnosis and intervention. Published in Science Advances, the study's findings could allow for the development of novel, more personalized therapeutics.

Researchers at the Icahn School of Medicine at Mount Sinai, New York, New York, identified 3 major molecular subtypes of Alzheimer that correspond to varying combinations of multiple dysregulated biological pathways that lead to brain degeneration.

The study's analysis revealed subtype-specific molecular drivers in disease progression and identified the correspondence between these molecular subtypes and the existing Alzheimer disease animal modules. Those modules are used for mechanistic studies and testing candidate therapeutics. According to the researchers, this may partly explain why the drugs that succeeded in specific mouse models were not successful in human trials— the participants probably belonged to different molecular subtypes.

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Using a computational biology approach, researchers were able to illuminate the relationships among biological factors that could potentially drive the progression of Alzheimer, such as different types of RNA and clinical and pathological traits. Researchers analyzed 1543 samples across 5 brain regions in two cohorts of patients with Alzheimer disease and normal controls.

In both cohort studies, Alzheimer disease subtypes were independent of the patient's age and disease stage and replicated across multiple brain regions. Alzheimer disease's 2 neuropathological hallmarks are tau neurofibrillary and amyloid-beta plaque, but they are only significantly increased in some subtypes.

There is increasing evidence that disease progression and responses to interventions vary significantly among patients with Alzheimer disease. For example, patients can experience slow or rapid cognitive decline, and some experience psychosis or depression.

“Such differences strongly suggest there are subtypes of AD with different biological and molecular factors driving disease progression,” said lead author, Bin Zhang, PhD, director of the Center for Transformative Disease Modeling, New York, New York.

The study's findings could help discover disease biomarkers in living patients, despite the subtyping being performed post-mortem, researchers said.

“Our systematic identification and characterization of the robust molecular subtypes of AD reveal many new signaling pathways dysregulated in AD and pinpoint new targets,” Dr. Zhang said. “These findings lay down a foundation for determining more effective biomarkers for early prediction of AD, studying causal mechanisms of AD, developing next-generation therapeutics for AD and designing more effective and targeted clinical trials, ultimately leading to precision medicine for AD."

References

Neff A, Wang M, Vatansever S, et al. Molecular Subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets. Science Advances. 2021;7(2):eabb5398.

Mount Sinai researchers identify and characterize three molecular subtypes of Alzheimer’s disease [press release]. New York, NY: Mount Sinai; January 06, 2021.