Alzheimer's disease is the most prevalent cause of dementia, defined by the co-presence of amyloid and tau proteins, but researchers are moving away from the simplistic assumptions of linear causality proposed by the original amyloid hypothesis. Aging is a major risk factor for Alzheimer's disease and cannot be explained by the amyloid hypothesis. To fully assess the intrinsic link between aging and Alzheimer's disease, attempts have been made to gather evidence at the molecular, cellular, and systemic levels that will provide insights into Alzheimer's disease treatments or interventions.
Currently, about 55 million people worldwide are experiencing dementia, and more than half of these cases are Alzheimer's disease (AD). As the most common cause of dementia in older adults, Alzheimer's disease irreversibly deprives patients of memory and cognition. And long before cognitive function declines significantly, the state of multiple types of cells in the brain and their interactions begin to change.
In a recent research paper published in the journal Nature, an international team of researchers based on the analysis of 1.65 million human brain cells constructed two distinct trajectories of brain aging at the cellular level: normal aging or the development of Alzheimer's disease. The results reveal the order of changes in the cell populations associated with Alzheimer's disease during the occurrence and progression of the disease, especially the changes of specific neuronal subsets and glial cell subsets in the early stage of the disease, which is expected to provide guidance for innovative therapies for the treatment of Alzheimer's disease and the delay of brain aging.
In the study, scientists analyzed in detail brain samples donated by as many as 437 elderly volunteers. From each brain, researchers collected thousands of cells in the prefrontal cortex, the brain region most susceptible to Alzheimer's disease and aging, using cutting-edge single-cell RNA sequencing technology to read the genes expressed by each cell. Then, with the help of machine learning techniques, the researchers analyzed the data of all 1.65 million cells to determine the type of cells and cell-to-cell interactions, and finally constructed a comprehensive cell atlas of the prefrontal cortex in the elderly.
Because these donors were in different stages of normal aging or mild to severe Alzheimer's disease before their deaths, and their cognitive state was well documented, the researchers combined their brain cell data with this information to identify changes in different cell populations that are associated with Alzheimer's disease, distinguish them from normal aging, and determine how disease-related cellular changes occur sequentially as the disease progresses.
▲Schematic diagram of the research method and process (Image source: Reference [1])
The results of the study showed that there are two groups of lipid-associated microglia that are critical in the early stages of Alzheimer's disease. Microglia are immune cells that reside in brain tissue, and these two groups of lipid-associated microglia (APOE and GPNMB positive, and APOE, GPNMB, and TREM2 positive, respectively) drive the appearance of β amyloid deposition and mediate tau tangles, two of the most critical pathological features of Alzheimer's disease.
In addition to microglia, a subset of astrocytes has been significantly associated with rapid cognitive decline caused by tau protein.
▲Two microglial subsets and one astrocyte subset play a key role in the process of brain function change and cognitive impairment in turn (Image source: Reference [1])
In this study, the authors devised a method to mimic the dynamics of the cellular environment, i.e., to define the aging trajectory of the brain by changes in different cell populations, from which it is clear how the composition of cell populations may change at different stages of brain aging.
As the authors point out, the composition of cell populations may need to be regulated in order to maintain cognitive function in the brain, and the results of this study reveal the cell populations that can be targeted to intervene in the brain's trajectory toward Alzheimer's disease.
Alzheimer's disease (AD) is one of the major medical problems facing mankind, and by 2050, the number of Alzheimer's disease patients worldwide may triple.
Resources:
[1] Gilad Sahar Green et al., (2024) Cellular communities reveal trajectories of brain ageing and Alzheimer’s disease. Nature Doi: https://doi.org/10.1038/s41586-024-07871-6
[2] A cellular community in the brain drives Alzheimer’s disease. Retrieved Aug. 30, 2024 from https://www.eurekalert.org/news-releases/1055962