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.

Their observations, drawn from a meta-analysis of 89 studies published between January 2013 and January 2024, were published in JAMA Aug. 28.

“The Nobel Prize in Medicine or Physiology in 2019 was awarded for the discovery of how mammalian cells sense oxygen,” said Kim, the Rush S. Dickson Distinguished Professor of Medicine at UNC School of Medicine and co-leader of the UNC Lineberger Cancer Genetics Research Program. “One of the key components of this oxygen sensing pathway is the von Hippel-Lindau tumor suppressor gene, which is mutated in approximately 90% of kidney cancers. This deep understanding of kidney cancer biology has led to several important therapeutic advances in recent years.”

Kim trained as a post-doc with William G. Kaelin, Jr., MD, who was jointly awarded the 2019 Nobel Prize for demonstrating how the von Hippel-Lindau gene influences cellular responses to changing oxygen levels.

The American Cancer Society estimates that more than 81,500 people will be diagnosed with kidney cancer in the United States this year, and the disease will cause 14,300 deaths. While the incidence of kidney cancer has been increasing by approximately 1.5% annually in recent years, deaths have decreased by about 2% each year from 2016 to 2020.

This decline in deaths is largely due to improved treatments and early detection. “The majority of kidney cancer cases are now detected incidentally, often before symptoms appear,” said Kim. He noted that the widespread use of abdominal imaging for unrelated issues has led to the incidental diagnosis of kidney cancer. “More cases are being identified in earlier stages when the cancer is typically more responsive to treatment.”

Cigarette smoking and being overweight are major risk factors for kidney cancer and are linked to nearly half of the cases in the United States. Other risk factors include high blood pressure, a family history of kidney cancer, workplace exposure to certain chemicals, and hereditary conditions, such as von Hippel-Lindau disease.

Current treatment approaches include surgery to remove part or all of the kidney, ablation using targeted heat or cold to destroy the tumor, or active surveillance with imaging technologies to monitor the tumor. For cancers that have metastasized, or spread beyond the kidney, newer treatment options include immune checkpoint inhibitors, tyrosine kinase inhibitors, or a combination of the two approaches.

“Advanced, metastatic kidney cancer is highly treatable with targeted therapy, immunotherapy or a combination of these newer therapies,” said Rose, associate professor of medicine at UNC School of Medicine. “Understanding the science underlying the disease has allowed for the rational development of therapies that have positively affected many patients the past two decades.”