Researchers from VIB, KU Leuven, UK DRI, and Muna Therapeutics, with funding including support from the ERC, have identified key biological changes that may help determine whether changes in the brain in Alzheimer’s disease ultimately lead to dementia.
Using brain tissue donated from older adults with and without cognitive decline and samples from cognitively healthy centenarians, the research team uncovered distinct cellular programs and immune cell states associated with both disease progression and resistance. The findings, published in Nature Medicine, point to changes in microglia, the brain’s resident immune cells, as a potentially important focus for future Alzheimer’s treatments.
“This has been an exciting journey with many partners. This study is based entirely on human donor material and provides insight into certain recovery mechanisms in the progression from Alzheimer’s disease to dementia,” said Professor Bart de Strooper (VIB-KU Leuven Neuroscience Center, University of Leuven), ERC grant recipient and one of the study’s co-senior authors.
Why Alzheimer’s disease doesn’t necessarily cause dementia
Alzheimer’s disease affects more than 55 million people worldwide. This is commonly associated with the accumulation of amyloid-beta plaques and tau tangles in the brain. However, these biological signs do not always correspond to a person’s mental state.
Some people may have significant amounts of plaque and plaque buildup but remain cognitively healthy. This has led scientists to focus more on how brain cells respond to these abnormal proteins, rather than simply measuring how much pathology is present.
Microglia appear to be particularly important. These immune cells help monitor and protect the brain, but their behavior can change dramatically as Alzheimer’s disease progresses. Understanding these changes may help researchers explain why some people remain resilient and identify new ways to prevent cognitive decline.
New findings suggest that people can resist damage associated with Alzheimer’s disease through multiple biological pathways. By comparing brain tissue from people with dementia, people without dementia, and cognitively healthy centenarians (people over 100 years old), researchers identified different microglial responses associated with protection from the effects of disease.
“A better understanding of how the brain resists disease will open new avenues for treatments to prevent neurodegeneration and dementia,” added the study’s co-senior author Professor Mark Fiers (VIB-KU Leuven).
Mapping severe Alzheimer’s disease transition
To investigate how resilience develops, the research team combined two advanced methods that examine tissues at the level of individual cells: spatial transcriptomics and single-cell sequencing.
These techniques allowed the researchers to identify six distinct tissue domains that appear to represent different stages of Alzheimer’s disease progression. One particularly important transition separated regions dominated by amyloid-β plaques from regions associated with tau pathology and neurodegeneration.
This change was accompanied by major changes in microglial behavior.
Early in the disease process, microglia entered an inflammatory state associated with amyloid plaques. At later stages, they transitioned to another antigen-presenting state that co-occurs with tau pathology.
Antigen presentation is the process by which immune cells present molecular substances to help coordinate the immune response. In this case, this change could mark a biological tipping point that helps determine whether Alzheimer’s pathology continues toward brain cell damage and dementia.
Two biological pathways to Alzheimer’s disease resilience
Researchers also found that resilience doesn’t look the same for everyone.
People in their 80s who developed amyloid plaques but did not have dementia showed an early microglial response. However, their microglia did not transition to the later immune state associated with disease progression.
Centenarians took a different path. Although their brains activated later microglial programs, this response occurred primarily independent of tau accumulation.
In other words, cellular states associated with neurodegeneration in some people appeared to be dissociated from deleterious effects in others. This suggests that resilience is not just about avoiding Alzheimer’s pathology. It may also depend on how the brain controls, redirects, or adapts its response to the medical condition.
New directions for Alzheimer’s disease treatment
The results may support the development of more precise treatments for Alzheimer’s disease.
Rather than focusing solely on clearing amyloid plaques, future treatments may aim to maintain beneficial early microglial activity or influence the transition between different microglial states. Molecules involved in these changes may represent valuable therapeutic targets.
Timing can also be important. Treatment may be most effective before the brain reaches a stage where inflammatory activity is associated with tau pathology, neurodegeneration, and cognitive decline.
“These findings open new opportunities to target microglial status, particularly pathways such as TREM2, and extend resilience rather than simply focusing on plaque clearance. We are excited to continue this work and understand the causal role of microglial migration, which may lead to the identification of new therapeutic approaches to slow or prevent disease progression,” concluded Niels Plass, CSO of Muna Therapeutics.
