Three molecular subtypes of Alzheimer's identified

Researchers at the Icahn School of Medicine at Mount Sinai have identified three major molecular subtypes of Alzheimer’s disease (AD) using data from RNA sequencing. Their study, published in the journal Science Advances, advances our understanding of the mechanisms of AD and could pave the way for developing novel, personalised therapeutics.

Alzheimer’s disease is the most common form of dementia, but it is quite diverse in its biological and pathological manifestations. Some patients have slow cognitive decline while others decline rapidly; some have significant memory loss and an inability to remember new information while others do not; and some patients experience psychosis and/or depression while others do not. According to Dr Bin Zhang, Director of the Mount Sinai Center for Transformative Disease Modeling and lead author of the new study, “Such differences strongly suggest there are subtypes of AD with different biological and molecular factors driving disease progression.”

To identify the molecular subtypes of AD, Mount Sinai researchers used a computational biology approach to illuminate the relationships among different types of RNA, clinical and pathological traits, and other biological factors that potentially drive the disease’s progress. The research team analysed RNA-sequencing data of more than 1500 samples across five brain regions from hundreds of deceased patients with AD and normal controls, and identified three major molecular subtypes of AD. These AD 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. Tau neurofibrillary tangle and amyloid-beta plaque, two neuropathological hallmarks of AD, are significantly increased only in certain subtypes.

Many recent studies have shown that an elevated immune response may help cause Alzheimer’s. However, more than half of AD brains don’t show increased immune response compared to normal healthy brains. The analysis further revealed subtype-specific molecular drivers in AD progression in these samples.

The research also identified the correspondence between these molecular subtypes and the existing AD animal models used for mechanistic studies and for testing candidate therapeutics, which may partially explain why a vast majority of drugs that succeeded in certain mouse models failed in human AD trials, which likely had participants belonging to different molecular subtypes.

Although the subtyping was performed post-mortem using the patients’ brain tissue, the researchers said that if the findings were validated by future studies, they could lead to the identification in living patients of biomarkers and clinical features associated with these molecular subtypes and earlier diagnosis and intervention.

“Our systematic identification and characterisation of the robust molecular subtypes of AD reveal many new signalling 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.

“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.”

Image credit: ©stock.adobe.com/au/Urupong

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