Using donated brain tissue from older adults with and without cognitive decline, along with samples from cognitively healthy centenarians, the team uncovered distinct cellular programs and immune cell states linked to 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. 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 (VIB-KU Leuven Center for Neuroscience, KU Leuven), ERC grantee and one of the co-senior authors of the study.

Why Alzheimer's Pathology Does Not Always Cause Dementia

Alzheimer's disease affects more than 55 million people worldwide. It is commonly associated with the buildup of amyloid-β plaques and tau tangles in the brain. However, these biological signs do not always match a person's mental condition.

Some people accumulate substantial amounts of plaques and tangles yet remain cognitively healthy. This has led scientists to focus more closely on how brain cells react to these abnormal proteins, rather than simply measuring how much pathology is present.

Microglia appear to be especially important. These immune cells help monitor and protect the brain, but their behavior can change dramatically as Alzheimer's advances. By understanding those changes, researchers may be able to explain why some people remain resilient and identify new ways to prevent cognitive decline.

The new findings suggest that people can resist Alzheimer's related damage through more than one biological pathway. By comparing brain tissue from people with dementia, people without dementia, and cognitively healthy centenarians (people over the age of 100 years), the researchers identified different microglial responses associated with protection from the disease's effects.

"Understanding better how the brain resists the disease will provide new avenues towards therapies to prevent neurodegeneration and dementia," adds Prof. Mark Fiers (VIB-KU Leuven), co-senior author of the study.

Mapping a Critical Alzheimer's Transition

To investigate how resilience develops, the team combined two advanced methods that examine tissue at the level of individual cells (spatial transcriptomics and single-cell sequencing).

These technologies allowed the researchers to identify six distinct tissue domains that appeared to represent different stages of Alzheimer's progression. One especially important transition separated regions dominated by amyloid-β plaques from those associated with tau pathology and neurodegeneration.

That shift was accompanied by a major change in the behavior of microglia.

During the earlier stages of the disease process, microglia entered an inflammatory state linked to amyloid plaques. At a later stage, they moved into a different antigen-presenting state that appeared at the same time as tau pathology.

Antigen presentation is a process in which immune cells display molecular material to help coordinate an immune response. In this case, the change may mark a biological turning point that helps determine whether Alzheimer's pathology continues toward brain cell damage and dementia.

Two Biological Paths to Alzheimer's Resilience

The researchers also found that resilience did not look the same in every person.

Octogenarians who had developed amyloid plaques but remained free of dementia showed the early microglial response. However, their microglia did not move into the later immune state associated with disease progression.

Centenarians followed a different route. Their brains activated the later microglial program, but this response occurred largely without being tied to tau accumulation.

In other words, a cellular state that was associated with neurodegeneration in some people appeared to be separated from damaging effects in others. This suggests that resilience is not simply a matter of avoiding Alzheimer's pathology. It may also depend on how the brain controls, redirects, or adapts its response to that pathology.

A New Direction for Alzheimer's Treatment

The results could support the development of more precise Alzheimer's therapies.

Instead of focusing only on removing amyloid plaques, future treatments might aim to preserve beneficial early microglial activity or influence the transition between different microglial states. Molecules involved in these shifts could become valuable therapeutic targets.

Timing may also be critical. Treatments could be most effective before the brain reaches the point where inflammatory activity becomes connected to tau pathology, neurodegeneration, and cognitive decline.

"These findings open new opportunities to target microglial states -- especially pathways such as TREM2 -- and extend resilience rather than simply focusing on plaque removal. We are excited to continue this journey and understand the causal role of microglial transitions leading to the identification of novel therapeutic approaches to delay or prevent disease progression," concludes Niels Plath, CSO of Muna Therapeutics.