Scientists have identified a key transition in brain immune cells that may determine whether Alzheimer's pathology leads to dementia. The research, based on human brain tissue, highlights distinct microglial responses associated with resilience or decline.
Researchers from VIB and KU Leuven, along with collaborators at the UK-DRI and Muna Therapeutics, examined donated brain samples from older adults and cognitively healthy centenarians. They used spatial transcriptomics and single-cell sequencing to map six tissue domains representing different stages of disease.
The team found that microglia shift from an inflammatory state tied to amyloid plaques to an antigen-presenting state coinciding with tau pathology. This change appears to mark a critical point where Alzheimer's may advance toward neurodegeneration.
Resilience pathways differed by age group. Octogenarians without dementia retained the early microglial response without progressing further, while centenarians activated the later program largely without tau buildup.
"These findings open new opportunities to target microglial states -- especially pathways such as TREM2 -- and extend resilience," said Niels Plath of Muna Therapeutics. The work was published in Nature Medicine.
