CSF sTREM2 is associated with distinct microglial responses with separate effects on Alzheimer's pathology in the disease's trajectory

Topic: Brain proteins, microglia and lab models

There is significant evidence that microglia contribute to neuroinflammation and neurotoxicity in AD 1,2 , yet there is also evidence to the contrary. Result TREM2 shows very significant ( p <0.001) associations with p ‐ and t‐tau in both MCI groups (r=0.618 and 0.615 in Aβ‐MCI, and r=0.507 and 0.477 in Aβ+MCI) yet none in AD. TREM2 also shows a very significant association ( p <0.001) with Aβ 1‐42 in Aβ‐MCI (r=0.401), and significant associations in Aβ+MCI and AD (r=0.203, p = 0.016; r=0.303, p = 0.004). Finally, Aβ 1‐42 is associated with GAP43 in Aβ‐MCI and AD (r=0.304, p = 0.003; r=0.218, p = 0.040) but not in Aβ+MCI, at which stage we observe the only negative association between amyloid and ADAS_Cog13 (r=‐0.263, p = 0.002). In Aβ+MCI, the microglial response is associated with preserved cognition, suggesting a neuroprotective phenotype has emerged in response to high amyloid load.

Key findings

• There is significant evidence that microglia contribute to neuroinflammation and neurotoxicity in AD 1,2 , yet there is also evidence to the contrary.
• Result TREM2 shows very significant ( p <0.001) associations with p ‐ and t‐tau in both MCI groups (r=0.618 and 0.615 in Aβ‐MCI, and r=0.507 and 0.477 in Aβ+MCI) yet none in AD.
• TREM2 also shows a very significant association ( p <0.001) with Aβ 1‐42 in Aβ‐MCI (r=0.401), and significant associations in Aβ+MCI and AD (r=0.203, p = 0.016; r=0.303, p = 0.004).
• Finally, Aβ 1‐42 is associated with GAP43 in Aβ‐MCI and AD (r=0.304, p = 0.003; r=0.218, p = 0.040) but not in Aβ+MCI, at which stage we observe the only negative association between amyloid and ADAS_Cog13 (r=‐0.263, p = 0.002).
• In Aβ+MCI, the microglial response is associated with preserved cognition, suggesting a neuroprotective phenotype has emerged in response to high amyloid load.

Why it matters

This study found that a marker of microglial activity, CSF sTREM2, was associated with Alzheimer's pathology differently at different stages of the disease. In one group with mild cognitive impairment and high amyloid, the microglial response was associated with preserved cognition, suggesting a possible protective role.

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Study details

• Participants89
• Evidence strengthLow

Read the original

• DOI: 10.1002/alz70856_100766
• PubMed: 41447298
• Original source →
• Free full text: Alzheimer s & Dementia →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{tuil2025-41447298,
  author  = {Tuil, Marie Emilie and Allehyany, Bshaier and Punnota, Rifa Sanjida and Edison, Paul},
  title   = {{CSF sTREM2 is associated with distinct microglial responses with separate effects on Alzheimer's pathology in the disease's trajectory}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70856_100766},
  pmid    = {41447298},
  url     = {https://doi.org/10.1002/alz70856_100766}
}

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