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 and published their findings in Science Advances, according to a press release.
RNA is a genetic molecule similar to DNA that encodes the instructions for making proteins, while RNA sequencing is a technology that reveals the presence and quantity of RNA in a biological sample such as a brain slice.
There is growing evidence that disease progression and responses to interventions differ significantly among Alzheimer’s patients. 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 associated with AD while others do not.
To identify the molecular subtypes of AD, the 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 analyzed RNA-sequencing data of more than 1,500 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 described by the researchers was performed postmortem 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.
