Researchers identify key cellular interactions driving Alzheimer’s and aging

An analysis of more than 1.6 million brain cells from older adults has captured the cellular changes that occur in the early stages of Alzheimer’s disease, potentially revealing new pathways for preventing the most common cause of dementia in older individuals.

The study also identified a second community of cells that drives the older brain onto a different path that does not lead to Alzheimer’s disease.

“Our study highlights that Alzheimer’s disease is a disease of many cells and their interactions, and not just a single type of dysfunctional cell,” said Columbia neurologist Philip De Jager, who led the study along with Vilas Menon, assistant professor of neurological sciences at Columbia University Vagelos. College of Physicians and Surgeons, and Naomi Habib of the Hebrew University of Jerusalem.

“We may need to modify cellular communities to maintain cognitive function, and our study reveals points in the chain of events leading to Alzheimer’s disease where we may be able to intervene.”

Crunching data from 1.6 million brain cells

The study was an engineering marvel, cleverly combining new molecular technologies, machine learning techniques and a large collection of brains donated by older adults.

While previous studies of brain samples from Alzheimer’s patients have provided insight into molecules involved in the disease, they have not revealed many details about where in the long chain of events that lead to Alzheimer’s disease those genes play a role and which cells are involved in each step. are involved. the process.

Previous studies have analyzed brain samples as a whole and lost all cellular details. We now have tools to view the brain at a finer resolution, at the level of individual cells. When we couple this with detailed information about the cognitive state of brain donors before death, we can reconstruct brain aging trajectories from the earliest stages of the disease.”

Philip De Jager, neurologist from Columbia

The new analysis required more than 400 brains, which were provided by the Religious Orders Study and the Memory & Aging Project at Rush University in Chicago.

Within each brain, the researchers collected several thousand cells from a brain region affected by Alzheimer’s disease and aging. Each cell was then put through a process – single-cell RNA sequencing – that provided a readout of the cell’s activity and which of its genes were active.

Data from all 1.6 million cells was then analyzed by algorithms and machine learning techniques developed by Menon and Habib to identify the types of cells in the sample and their interactions with other cells.

“These methods have allowed us to gain new insights into possible sequences of molecular events that result in altered brain function and cognitive impairment,” says Menon. “This was only possible thanks to the large number of brain donors and cells from which the team was fortunate to generate data.”

Aging vs. Alzheimer’s

Because the brains came from people at different points in the disease process, the researchers were able to solve a major challenge in Alzheimer’s research: identifying the sequence of changes in cells involved in Alzheimer’s disease and distinguishing these changes from the changes associated with normal brain aging.

“We propose that two different types of microglial cells – the brain’s immune cells – initiate the process of amyloid and tau accumulation that define Alzheimer’s disease,” says De Jager.

After pathology accumulates, several cells called astrocytes play a key role in altering electrical connectivity in the brain, leading to cognitive impairment. The cells communicate with each other and bring in additional cell types that lead to a profound disruption of the way the human brain functions.

“These are exciting new insights that could guide innovative therapeutic development for Alzheimer’s disease and brain aging,” says De Jager.

“By understanding how individual cells contribute to the different stages of the disease, we will know the best approach to reduce the activity of the pathogenic cellular communities in each individual, returning brain cells to health,” says De Jager.