International Business Department           Liu Bojia           September 04, 2024

  Today, around 55 million people worldwide are experiencing dementia, with more than half of these cases falling under

the category of Alzheimer's disease (AD). As the most common cause of dementia in the elderly, Alzheimer's disease 

progressively and irreversibly robs patients of their memory and cognitive abilities. And long before cognitive decline 

becomes apparent, the state of several types of cells in the brain and their interactions begin to change.

  In a new research paper published in the journal Nature, an international team of researchers has constructed two 

distinct trajectories of brain ageing at the cellular level, based on the analysis of 1.65 million individual brain cells: 

whether it is normal ageing or the development of Alzheimer's disease. The findings reveal the sequence of changes 

in cellular taxa associated with Alzheimer's disease during the development of the disease, particularly in specific 

neuronal subpopulations and glial cell subpopulations in the early stages of the disease, and are expected to provide 

guidance for innovative therapies for treating Alzheimer's disease and slowing down brain aging.

  In this study, scientists analysed in detail brain samples donated by up to 437 elderly volunteers. From each brain, 

the 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 in each cell. 

The researchers then analysed the data from all 1.65 million cells with the help of machine learning techniques to 

determine cell types and cell-cell interactions, ultimately constructing a comprehensive cellular picture of the prefrontal 

cortex in older adults.

  Since these donors were at different stages of normal aging or mild to severe Alzheimer's disease before they died, and

their cognitive status was well documented during their lifetime, the researchers combined their brain cell data with this

information to identify the changes associated with Alzheimer's disease in different cellular taxa, to differentiate them

from normal aging, and to determine how the disease-associated cellular changes may occur in sequence as the disease

progresses.

  The findings show that two groups of lipid-associated microglia 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), one group drives the emergence of β-amyloid 

deposition, and one group mediates tau protein tangles, the two events that are the most critical pathological features 

of Alzheimer's disease.

  In addition to microglia, a subpopulation of astrocytes is significantly associated with tau protein-induced rapid cognitive

decline.

  In this study, the authors devised a method to simulate the dynamics of the cellular environment, i.e., the aging 

trajectory of the brain is defined by changes in different cell populations, from which it is clear how the composition of 

cellular taxa may change at different stages of brain aging.

  As the study authors point out, modulating the composition of cell populations may be necessary to maintain cognitive 

function in the brain, and the results of this study reveal cell populations that could be targeted for intervention in the 

brain's trajectory toward Alzheimer's disease.