A comprehensive analysis involving over 1.6 million brain cells from elderly individuals has shed light on the cellular changes that take place in the initial phases of Alzheimer’s disease. This discovery may lead to new strategies for preventing this prevalent form of dementia among older adults.
The research has also uncovered an additional group of cells that guide the aging brain down a different pathway, one that does not culminate in Alzheimer’s disease.
Columbia neurologist Philip De Jager, who spearheaded the study alongside Vilas Menon, an assistant professor at Columbia University Vagelos College of Physicians and Surgeons, and Naomi Habib from the Hebrew University of Jerusalem, remarked, “Our research underlines that Alzheimer’s is a multi-cellular disease driven by interactions among various cells, rather than being solely due to one type of malfunctioning cell.”
“There may be the need to adjust these cellular communities to maintain cognitive function, and our findings pinpoint moments in the progression towards Alzheimer’s where intervention could be possible.”
Analyzing data from 1.6 million brain cells
This study represented a significant technical achievement, ingeniously integrating cutting-edge molecular technologies, machine-learning methods, and a vast collection of brains donated by aging adults.
Prior studies analyzing brain samples from Alzheimer’s patients have unveiled insights into the molecules linked to the disease, but they haven’t provided comprehensive details on where within the lengthy progression towards Alzheimer’s specific genes are active or which cells are involved at each stage.
De Jager comments, “Earlier research examined brain samples as a whole, resulting in a loss of all cellular specifics. We now possess tools that enable us to investigate the brain with remarkable detail at the level of individual cells. Coupled with thorough information regarding the cognitive conditions of donors prior to their passing, we can construct trajectories of brain aging from the disease’s earliest stages.”
The novel analysis utilized over 400 brains sourced from the Religious Orders Study and the Memory & Aging Project, both based at Rush University in Chicago.
Researchers extracted thousands of cells from a brain region affected by Alzheimer’s and aging from each brain. Each cell underwent a procedure called single-cell RNA sequencing, which provided insights into the cell’s activity and the genes that were active.
Algorithms and machine-learning techniques devised by Menon and Habib were then employed to analyze data from all 1.6 million cells to identify the types of cells present in the samples and their interactions with each other.
Menon states, “These methodologies enabled us to uncover new perspectives on the potential molecular sequences that lead to changes in brain function and cognitive decline. This achievement was only attainable due to the extensive number of brain donors and cells from which our team was able to gather data.”
Distinguishing Aging from Alzheimer’s
The diversity in brain samples from individuals at different stages of the disease process allowed researchers to address a significant challenge in Alzheimer’s research: determining the sequence of cellular changes associated with Alzheimer’s and differentiating them from the changes affiliated with regular brain aging.
De Jager proposes that two distinct types of microglial cells—the brain’s immune cells—initiate the accumulation of amyloid and tau proteins characteristic of Alzheimer’s disease.
Once these pathological elements have developed, another group of cells known as astrocytes plays a crucial role in modifying electrical connectivity in the brain, contributing to cognitive decline. These cells interact with one another and recruit additional cell types, resulting in significant disruptions to normal brain function.
De Jager expresses enthusiasm for these new insights, stating, “They can inform the development of innovative treatments for Alzheimer’s and age-related changes in the brain.” He adds, “By comprehending how individual cells impact various stages of the disease, we can identify the most effective methods to reduce the detrimental activity of these pathological cellular communities, restoring brain cells to a healthier state.”
