Brain Autopsies Revealed a Potential Culprit Behind Alzheimer's

Scientists have found that immune cells in Alzheimer’s brains behave differently from those in the brains of people without the condition - a finding that could open the door to new treatments.

In a study published in 2023, researchers analysing donated human brain tissue reported that microglia in the brains of people with Alzheimer’s were more often in a pre-inflammatory state, which may make them less likely to protect the brain.

What microglia do in a healthy brain

Microglia are immune cells that help keep the brain healthy by clearing waste and supporting normal brain function.

When responding to infection or when removing dead cells, these adaptable shape-shifters can change from a more spindly form into one that is more mobile, allowing them to engulf invaders and debris. They also “prune” synapses during development, helping to shape the brain’s circuitry so it can function properly.

Watch the video below for a summary of the research:

Microglia, inflammation and Alzheimer’s disease

Exactly what role microglia play in Alzheimer’s remains less clear. However, in people living with this devastating neurodegenerative disease, some microglia appear to react too strongly and may trigger inflammation that contributes to the death of brain cells.

So far, clinical trials testing anti-inflammatory medicines for Alzheimer’s have not shown meaningful benefits.

University of Washington study: microglia in Alzheimer’s brains

To examine microglia more closely in Alzheimer’s disease, University of Washington neuroscientists Katherine Prater and Kevin Green, working with colleagues across several US institutions, studied microglial gene activity using brain autopsy samples from research donors - 12 people who had Alzheimer’s and 10 healthy controls.

Using a new approach designed to improve single-nucleus RNA sequencing, the team was able to identify, in detail, 10 distinct clusters of microglia within the brain tissue. These clusters were defined by their particular patterns of gene expression, which influence what the cells do.

Three of the clusters had not been described previously, and one of these newly identified clusters appeared more frequently in people with Alzheimer’s disease. In that microglia type, genes linked to inflammation and cell death were switched on.

Key findings: a shift towards a pre-inflammatory state

Across the samples, the researchers found that microglia clusters in the brains of people with Alzheimer’s disease were more likely to be in a pre-inflammatory state.

This indicates they were more prone to producing inflammatory molecules that can harm brain cells and may contribute to the progression of Alzheimer’s disease.

In addition, the microglia types seen in the brains of people with Alzheimer’s disease were less likely to be protective, reducing their ability to do their share of clearing dead cells and waste - and supporting healthy ageing in the brain.

The scientists also propose that microglia may shift from one type to another over time. That means it is not possible simply to inspect one brain and state with certainty which microglia type a person has overall; instead, tracking how microglia change over time could help clarify how they influence Alzheimer’s disease.

"At this point, we can't say whether the microglia are causing the pathology or whether the pathology is causing these microglia to alter their behavior," said Prater.

Why these microglia clusters matter for future treatments

The work strengthens scientists’ understanding of how microglia may be involved in Alzheimer’s disease and suggests that particular microglia clusters could become targets for new therapies.

The researchers are optimistic that this line of investigation could ultimately support the development of treatments that improve the lives of people with Alzheimer’s disease.

"Now that we have determined the genetic profiles of these microglia, we can try to find out exactly what they are doing and hopefully identify ways to change their behaviors that may be contributing to Alzheimer's disease," Prater said.

"If we can determine what they are doing, we might be able to change their behavior with treatments that might prevent or slow this disease."

The study has been published in Nature Aging.

An earlier version of this article was published in August 2023.