Microglia transitions act as critical turning point in Alzheimer's

Researchers from VIB, KU Leuven, the UK-DRI and Muna Therapeutics, funded by, among others, ERC, have uncovered a critical biological transition that may determine whether Alzheimer's disease pathology leads to dementia. Studying brain tissue from older adults with and without cognitive decline, as well as cognitively healthy centenarians, the team identified distinct cellular programs and immune-cell states associated with disease progression and resilience. Their findings, published in Nature Medicine, suggest that changes in microglia—the brain's resident immune cells—could represent an important target for future Alzheimer's therapies.

"This has been an exciting journey with many partners. The study, entirely based on human donor material, provides insight into one type of resilience mechanism in the progression of AD to dementia," says Prof. Bart De Strooper, Professor at KU Leuven and VIB Group leader at the VIB-KU Leuven Center for Neuroscience, one of the co-senior authors of the study.

Alzheimer's disease affects more than 55 million people worldwide and is marked by the accumulation of amyloid-β plaques and tau tangles in the brain. Yet the relationship between these hallmarks and dementia is not straightforward: some individuals remain cognitively healthy despite having plaques and tangles. Scientists increasingly believe that the answer lies in how different brain cells respond to these proteins. Among the most important players are microglia, the brain's immune cells, whose activity changes dramatically as the disease progresses. Understanding these cellular responses could reveal why some people are resilient to Alzheimer's disease and help identify new therapeutic targets.

The new study reveals that individuals who remain cognitively healthy despite Alzheimer's pathology do so through distinct biological mechanisms. By comparing the brains of people with and without dementia, as well as cognitively healthy centenarians (people over the age of 100 years), the researchers identified unique microglial responses associated with resilience against Alzheimer's disease, providing new insights into how the brain can resist the effects of the condition.