A new study has provided a compelling answer to a long-standing question in ageing research, explicitly addressing whether Alzheimer’s disease-dementia is merely a form of accelerated ageing or if there exists a distinct pathway that could lead to healthier brain ageing. This comprehensive international research effort involved mapping 1.65 million cells from 437 ageing brains, revealing diverse cellular changes associated with ageing. The study distinguished two significant pathways: one leading to Alzheimer’s disease and another representing an alternative, healthier form of brain ageing. Furthermore, the research highlighted specific cellular signatures that could predict the advancement of the disease once they manifest in the ageing brain. These findings not only provide deeper insights into the development of Alzheimer’s disease but also differentiate it from normal brain ageing. Notably, the changes in brain cells identified by the researchers may occur several years before any clinical symptoms or memory loss, thus opening avenues for personalised preventive medicine. This could potentially modify disease progression and improve outcomes for individuals at risk.
The research was led by an impressive international team, including notable contributions from Dr Naomi Habib and Gilad Green from the Hebrew University of Jerusalem, alongside Dr Philip L. De Jager and Dr Vilas Menon from Columbia University Irving Medical Center, Dr David Bennett from Rush Alzheimer’s Disease Center, and Dr Hyun-Sik Yang from Harvard Medical School. Published in the prestigious journal Nature, the study unveiled critical insights into the cellular dynamics that drive brain ageing and the events that lead to the onset and progression of Alzheimer’s disease (AD). By utilising one of the most significant resources in the brain ageing field, alongside innovative machine learning algorithms, the researchers were able to delineate distinct cellular paths in brain ageing, setting a solid foundation for the development of personalised therapies targeting Alzheimer’s disease.
This study detailedly mapped the brain’s cellular environment, analysing an extensive dataset of 1.65 million single-nucleus RNA sequencing profiles from the prefrontal cortex of older adults, part of the ROSMAP cohort at Rush University in Chicago, USA. Through this extensive data, the researchers identified specific groups of glial and neuronal cells associated with traits linked to Alzheimer’s disease. Furthermore, they employed a novel algorithm called BEYOND to model the intricate dynamics within brain cells throughout ageing and disease progression. This innovative approach revealed two distinct ageing pathways, each characterised by gradual, coordinated changes within specific cellular communities. Notably, one pathway leads to Alzheimer’s disease. It is marked by the progressive onset of dementia, characterised by memory loss and cognitive decline, while the other path represents a non-Alzheimer’s, healthier form of brain ageing.
The importance of this research extends to the foundational discoveries regarding the role of glial cells in Alzheimer’s disease. Previously, microglia and astrocytes, supportive cells crucial for brain function, were not fully recognised for their potential role in the progression of Alzheimer’s disease. However, recent findings, including those from a 2023 study published in Nature Neuroscience by the same research team, have started elucidating these cells’ specific roles. The latest study identified two distinct subsets of microglial cells, both associated with altered lipid metabolism, with one subset predicted to drive the accumulation of amyloid-β plaques—the initial hallmark pathology of Alzheimer’s disease—and another likely contributing to the subsequent buildup of neurofilament tangles. These discoveries underscore the complex interactions between different brain cells in Alzheimer’s progression and highlight the crucial role of glial cells.
The implications of these findings are significant for the development of personalised treatments. Dr Naomi Habib remarked on the unique insights gained from this research, noting that it has laid a cellular foundation for understanding the distinct pathways leading to Alzheimer’s and alternative ageing processes. By identifying specific cells involved in each unique path of brain ageing, the research paves the way for the early identification of individuals at risk of Alzheimer’s disease and for developing targeted treatments designed to promote healthy ageing. This study marks a pivotal step in understanding the cellular basis of Alzheimer’s disease and opens the door to innovative treatment strategies that could potentially alter the disease’s trajectory.
More information: Gilad Sahar Green et al, Cellular communities reveal trajectories of brain ageing and Alzheimer’s disease, Nature. DOI: 10.1038/s41586-024-07871-6
Journal information: Nature Provided by The Hebrew University of Jerusalem
