A study of 1.6 million brain cells revealed early cellular changes in Alzheimer’s and intervention opportunities, using advanced technology to differentiate disease progression from normal aging.
An analysis of over 1.6 million brain cells from older adults has identified the cellular changes that occur in the early stages of Alzheimer’s disease. These findings could potentially uncover new strategies for preventing the most common cause of dementia in older adults.
The study also identified a second community of cells that drives the older brain down a different path that does not lead to Alzheimer’s disease.
“Our study highlights that Alzheimer’s is a disease of many cells and their interactions, not just a single type of dysfunctional cell,” says Columbia neurologist Philip De Jager, who led the study 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 preserve cognitive function, and our study reveals points along the sequence of events leading to Alzheimer’s where we may be able to intervene.”
Crunching data from 1.6 million brain cells
The study was a technical marvel, cleverly combining new molecular technologies, machine-learning techniques, and a large collection of brains donated by aging adults.
Though previous studies of brain samples from Alzheimer’s patients have provided insights into molecules involved in the disease, they have not revealed many details about where in the long sequence of events leading to Alzheimer’s those genes play a role and which cells are involved at each step of the process.
“Past studies have analyzed brain samples as a whole and they lose all cellular detail,” De Jager says. “We now have tools to look at the brain in finer resolution, at the level of individual cells. When we couple this with detailed information on the cognitive state of brain donors before death, we can reconstruct trajectories of brain aging from the earliest stages of the disease.”
The new analysis required over 400 brains, which were provided by the Religious Orders Study and the Memory & Aging Project based at Rush University in Chicago.
Within each brain, the researchers collected several thousand cells from a brain region impacted by Alzheimer’s and aging. Every cell was then run through a process—single-cell RNA sequencing—that gave a readout of the cell’s activity and which of its genes were active.
Data from all 1.6 million cells were then analyzed by algorithms and machine-learning techniques developed by Menon and Habib to identify the types of cells present in the sample and their interactions with other cells.
“These methods allowed us to gain new insights into potential sequences of molecular events that result in altered brain function and cognitive impairment,” Menon says. “This was only possible thanks to the large number of brain donors and cells the team was fortunate enough to generate data from.”
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 and distinguishing these changes from those associated with normal brain aging.
“We propose that two different types of microglial cells—the immune cells of the brain—begin the process of amyloid and tau accumulation that define Alzheimer’s disease,” De Jager says.
Then after the pathology has accumulated, different cells called astrocytes play a key role in altering electrical connectivity in the brain that leads to cognitive impairment. The cells communicate with each other and bring in additional cell types that lead to a profound disruption in the way the human brain functions.
“These are exciting new insights that can guide innovative therapeutic development for Alzheimer’s and brain aging,” De Jager says.
“By understanding how individual cells contribute to the different stages of the disease, we will know the best approach with which to reduce the activity of the pathogenic cellular communities in each individual, returning brain cells to their healthy state,” De Jager says.
Reference: “Cellular communities reveal trajectories of brain ageing and Alzheimer’s disease” by Gilad Sahar Green, Masashi Fujita, Hyun-Sik Yang, Mariko Taga, Anael Cain, Cristin McCabe, Natacha Comandante-Lou, Charles C. White, Anna K. Schmidtner, Lu Zeng, Alina Sigalov, Yangling Wang, Aviv Regev, Hans-Ulrich Klein, Vilas Menon, David A. Bennett, Naomi Habib and Philip L. De Jager, 28 August 2024, Nature.
DOI: 10.1038/s41586-024-07871-6
The study was funded by the National Institutes of Health, the Chan Zuckerberg Initiative, the Israel Science Foundation, the European Research Council, the Chinese Ministry of Science and Technology, the Myers Foundation, and the Alzheimer’s Association.
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2 Comments
Now eighty years of age with a family history of nearly subclinical non-IgE-mediated food allergies (e.g., Dr. Arthur F. Coca, by 1935) and dementia and a personal history of being a ‘worse’ but not ‘worst’ case scenario of Dr. Coca’s kind of allergies with two temporary nutritional deficiency related incidents of short-term memory problems, as a lay witness and investigator I find that the most likely cause of Alzheimer’s Disease is allergy related (e.g., inflammation leading to a high serum level of uric acid via xanthine oxidase reduction) acidic blood with the most damage done where the flow of acidic blood is the greatest; what the individual mostly focuses on. Having shared this widely for a decade or so, it’s obvious to me the primary research interest is in profitable medical treatments, not low cost prevention.
“We may need to modify cellular communities to preserve cognitive function, and our study reveals points along the sequence of events leading to Alzheimer’s where we may be able to intervene.” Modifying cellular communities throughout the brain is pretty ambitious, especially when all you are looking at are brains at a point in time that has been modified by drugs, which these people must have been taking.
The genetic determinism of all this is an amazingly limited view of the brain. The brain is not just affected by genes. It is also affected by the physical world, including the force of gravity. This is why sleep position has a central and vital influence on the brain and its circulation and pressure, which affects its function. NASA scientists know this about the brain, because without gravity fluid shifts to the head and brain in astronauts, causing migraines, eye pressure, and lots more. They test this on Earth by having people lie flat, the way most people sleep. I have studies sleep position and found, as did NASA, that head of bed elevation of anywhere from 10-30 degrees improves brain function. Head of bed elevation is already used for stroke, sleep apnea and glaucoma, and we showed it also helps with migraines. It is clearly also involved in dementia.
See my article, Heads Up! The Way You are Sleeping can be Killing You!
https://www.academia.edu/1483361/Heads_Up_The_Way_You_Are_Sleeping_May_Be_Killing_You_