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Tech & Science
Researchers identify immune cell shifts in the brain that may determine progression from Alzheimer’s pathology to dementia.
Scientists have pinpointed a critical biological transition in brain immune cells that may explain why some individuals with Alzheimer’s pathology avoid developing dementia. This discovery centers on microglia, the brain’s immune cells, and their changing states during disease progression.
Alzheimer’s disease research has traditionally focused on amyloid plaques and tau tangles, the disease’s hallmark features. However, some people with extensive plaque and tangle buildup maintain cognitive function until death, posing a longstanding scientific puzzle. A collaborative study by researchers from VIB, KU Leuven, the UK Dementia Research Institute, and Muna Therapeutics offers new insights into this phenomenon.
The study, published in Nature Medicine on June 4, 2026, investigated how brain cells respond to Alzheimer’s pathology rather than just measuring the presence of plaques and tangles. By analyzing brain tissue from older adults with varying cognitive statuses, including cognitively healthy centenarians, the researchers found that resilience to dementia may depend more on the brain’s immune response than on the amount of pathological protein accumulation.
Microglia are specialized immune cells responsible for maintaining neural health by clearing debris and responding to injuries. Their role in Alzheimer’s disease is complex, as they can either protect the brain or contribute to damage depending on their activation state.
Using advanced techniques such as spatial transcriptomics and single-cell sequencing, the team identified six distinct tissue states linked to different stages of Alzheimer’s. Early stages were characterized by amyloid plaque accumulation and an inflammatory microglial response. Later stages involved tau pathology, neurodegeneration, and a shift in microglial function toward an antigen-presenting state, which typically signals threats to other immune cells.
This transition in microglia may represent a pivotal biological tipping point influencing whether Alzheimer’s pathology advances to dementia.
The study revealed that cognitive resilience arises through multiple mechanisms. Among octogenarians with amyloid plaques but no cognitive decline, microglia exhibited an early inflammatory state but did not progress to the later immune state associated with disease advancement.
In contrast, centenarians displayed activation of the later microglial state, but this occurred largely independently of tau accumulation. These findings suggest that resilience is not solely about avoiding pathological changes but may involve the brain’s capacity to modify its immune response to preserve cognitive function.
Current Alzheimer’s treatments have focused on removing amyloid plaques, yet their impact on slowing cognitive decline remains limited. The new findings indicate that targeting microglial states and immune pathways, particularly those involving the TREM2 gene linked to Alzheimer’s risk and microglial activity, could offer alternative therapeutic avenues.
The researchers emphasize the importance of early intervention before inflammatory microglial responses become closely associated with tau pathology, highlighting a potentially narrow window for effective treatment.
Niels Plath, Chief Scientific Officer of Muna Therapeutics, stated, “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.”
The study titled “Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience” was authored by Ashley Lu and colleagues, including Bart De Strooper and Mark Fiers, and published in Nature Medicine. The DOI is 10.1038/s41591-026-04393-8.
