Do Brain Immune Cells Evolve Differently Depending on the Stages of Alzheimer’s Disease?

A new study reveals how the brain’s immune cells, called microglia, change their activity during the different phases of Alzheimer’s disease. Although these cells are few in number, they play a key role in the progression of the disease. Scientists analyzed cerebrospinal fluid samples from more than 800 individuals, ranging from healthy people to patients with advanced dementia. They identified 109 microglia-related proteins whose levels vary depending on the stage of the disease.

In the early stage, before symptoms appear, the detected proteins suggest activation of the innate immune system and increased cell mobility. This could reflect an initial brain response to eliminate the abnormal deposits associated with the disease. Among these proteins, some, such as APP, VEGFA, and ADGRE5, appear specific to this silent phase.

In contrast, in patients with dementia, the observed proteins indicate a more complex immune response. Adaptive immunity mechanisms and inflammatory signals become more pronounced. Proteins such as CCL2 and CTSH, linked to inflammation and antigen presentation, then dominate. These changes could explain why chronic inflammation worsens brain damage over time.

Researchers also noted that some proteins remain disrupted throughout the disease. This shows that microglia do not simply transition from one state to another but accumulate progressive dysfunctions. Further analysis isolated 18 proteins capable of precisely distinguishing the asymptomatic early stage from advanced dementia. These markers could help develop tests to monitor disease progression and assess treatment efficacy.

Age, a major risk factor, has little influence on these protein variations. Most of the observed changes are therefore directly related to the disease and not to normal aging. Moreover, these modifications are specific to Alzheimer’s disease and are not found in other forms of dementia, such as Lewy body dementia or frontotemporal dementia.

This study paves the way for a better understanding of the role of microglia in Alzheimer’s disease. It also suggests that targeting these immune cells could offer new therapeutic avenues to slow or alter the course of the disease. The identified proteins could serve as biomarkers to tailor treatments according to each patient’s stage.

Attributions and Sources

Origin of the Study

DOI: https://doi.org/10.1038/s43587-026-01088-0

Title: Microglia protein profiles in CSF across Alzheimer’s disease clinical stages

Journal: Nature Aging

Publisher: Springer Science and Business Media LLC

Authors: Elena-Raluca Blujdea; Pieter van Bokhoven; Pamela V. Martino-Adami; Victoria S. Marshe; Ellen M. Vromen; Yanaika S. Hok-A-Hin; Walter A. Boiten; David J. Irwin; Alice S. Chen-Plotkin; Afina W. Lemstra; Yolande Pijnenburg; Wiesje M. van der Flier; Oliver Peters; Julian Hellmann-Regen; Josef Priller; Anja Schneider; Jens Wiltfang; Frank Jessen; Emrah Düzel; Katharina Buerger; Robert Perneczky; Stefan Teipel; Christoph Laske; Frederic Brosseron; ; Lukas Preis; Daria Gref; Eike Jakob Spruth; Maria Gemenetzi; Klaus Fliessbach; Claudia Bartels; Ayda Rostamzadeh; Wenzel Glanz; Enise I. Incesoy; Daniel Janowitz; Michael Ewers; Boris-Stephan Rauchmann; Ingo Kilimann; Doreen Goerss; Sebastian Sodenkamp; Annika Spottke; Marie Kronmüller; Michael Wagner; Sandra Roeske; Marta del Campo; Ruud Wijdeven; Pieter-Jelle Visser; Betty M. Tijms; Philip L. De Jager; Alfredo Ramirez; Charlotte E. Teunissen; Lisa Vermunt