The brain resists dementia through an adapted immune response
A recent study reveals that Alzheimer’s disease does not inevitably develop in elderly individuals exposed to brain lesions. How brain cells respond to the accumulation of abnormal proteins, such as amyloid-beta and tau protein, determines whether dementia appears or not. These reactions do not follow a linear pattern but evolve through precise stages, marked by changes in the activity of the brain’s immune cells, called microglia.
Researchers analyzed brain samples from octogenarians, both with and without dementia, as well as from cognitively healthy centenarians despite significant amyloid-beta deposits. They identified six distinct cellular environments, representing a pathological continuum. A key point in this evolution occurs when amyloid-beta-related inflammation gives way to cellular programs associated with the tau protein. This transition is accompanied by a change in the state of microglia, shifting from an early inflammatory state to a more advanced state where they present antigens, a mechanism often linked to immune defense.
In octogenarians without dementia, microglia remain in an early inflammatory state and do not reach the advanced stage. In contrast, in centenarians, microglia activate this advanced stage without triggering tau accumulation. This suggests that these individuals have developed unique resistance mechanisms, allowing them to maintain cognitive function despite the presence of lesions.
This discovery highlights the importance of microglia in the progression or halt of the disease. Their ability to modulate their immune response could be a key to understanding why some people resist dementia. By adapting their activity, microglia appear to play a central role in protecting against neuronal degeneration, thus opening avenues for future therapies specifically targeting these cells.
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DOI: https://doi.org/10.1038/s41591-026-04393-8
Title: Human microglial transitions at the Aβ–tau inflection point associate with divergent pathways to dementia and resilience
Journal: Nature Medicine
Publisher: Springer Science and Business Media LLC
Authors: Ashley Lu; Wei-Ting Chen; Maria Dalby; Diego Sainz Garcia; Marisa Vanheusden; Luuk E. de Vries; Veerle van Lieshout; Araks Martirosyan; Katleen Craessaerts; Sebastiaan Moonen; Magdalena Zielonka; Iordana Chrysidou; Anke Misbaer; Leen Wolfs; Benjamin Pavie; Dick Swaab; Dietmar Rudolf Thal; Inge Huitinga; Annemieke Rozemuller; Susan Karijn Rohde; Marc Hulsman; Henne Holstege; Rita Balice-Gordon; Niels Plath; Mark Fiers; Bart De Strooper