Researchers identify a key biological tipping point in Alzheimer’s disease

Their findings, published in Nature Medicine, suggest that changes in microglia 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, provide 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, one of the co-last authors of the study and ERC grantee.

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. Increasing evidence suggests that differences in how brain cells respond to these proteins may help explain this variability. 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 help reveal why some people are resilient to Alzheimer’s disease and help identify new therapeutic targets.

The new study suggests 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.

'Understanding better how the brain resists the disease, will provide new avenues towards therapies to prevent neurodegeneration and dementia', adds Prof. Mark Fiers, co-last author of the study.

Mapping a key transition in Alzheimer’s disease

To investigate this resilience, the research team combined technologies that can analyse tissues at the level of single cells (spatial transcriptomics and single-cell sequencing), and they identified six distinct tissue domains representing different stages of Alzheimer’s disease progression. A key turning point emerged between domains associated primarily with amyloid-β plaques and those linked to tau pathology and neurodegeneration.

This transition was accompanied by a striking change in microglia. Early in the disease process, these cells adopted an inflammatory state associated with amyloid plaques. Later, they switched to a distinct antigen-presenting state that appeared alongside the emergence of tau pathology. The findings suggest that this cellular transition may represent a critical step determining whether Alzheimer’s pathology progresses toward dementia.

Two different routes to resilience

The study also revealed that resilience to Alzheimer’s disease can arise through different biological mechanisms. Octogenarians who accumulated amyloid plaques but remained free of dementia showed an early microglial response but did not transition into the later immune state associated with disease progression.

Centenarians displayed a different pattern. Although they activated the later microglial program, this response occurred largely independently of tau accumulation. In other words, a cellular state linked to neurodegeneration in some individuals appeared to be uncoupled from harmful effects in others. These findings suggest that resilience is not simply the absence of pathology, but the brain’s ability to alter how it responds to it.

These insights could help guide the development of more precise therapies. Molecules aimed at preserving beneficial early microglial responses and involved in microglial state transitions could represent valuable therapeutic targets. The results also raise the possibility that interventions targeting these processes may be most effective before later pathological changes become established.

'These findings open for 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 

Publication

Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience. Lu, et al. Nature Medicine, 2026. DOI: 10.1038/s41591-026-04393-8.

Funding

This research was supported by, among others, Muna Therapeutics, VIB, KU Leuven, the European Research Council (ERC), the UK DRI and the Research Foundation Flanders (FWO). For a complete list of funding sources, see the paper's acknowledgments.