Rethinking Anti-Inflammatory Therapy in Alzheimer’s Disease: From Broad Suppression to Stage–State–Space Neuroimmune Reprogramming
- 1Hwamei College of Life and Health Sciences, Zhejiang Wanli University, Ningbo 315100, China
- 2Zhejiang Key Laboratory of Intelligent Food Logistic and Processing, Yuyao Innovation Institute, Zhejiang Wanli University, Ningbo 315400, China
Abstract
Alzheimer's Disease (AD) is now understood as a biologically diverse condition, with amyloid and tau pathology evolving within dynamic neuroimmune networks. This challenges the traditional view that AD-related inflammation can be broadly suppressed therapeutically. We review evidence showing that neuroinflammation in AD is stage-dependent, cell-state-specific, spatially organized, and functionally complex. Microglia and astrocytes can aid in plaque containment, debris clearance, synaptic balance, metabolic adaptation, and tissue repair, but may also exacerbate injury through type-I interferon, inflammasome, complement, tumor necrosis factor, and lipid pathways. Many failed anti-inflammatory trials likely stem from mismatches in targets, timing, spatial considerations, pathway redundancy, and biomarker selection, rather than invalidating neuroinflammation as a therapeutic target. Recent single-cell and spatial transcriptomic, proteomic, metabolomic, and network-medicine studies offer a framework for precision intervention by identifying inflammatory endotypes, anatomical niches, and pathway modules. We propose the Stage-State-Space Neuroimmune Reprogramming Model (S3-NRM), aligning AD immunotherapy with disease stage, glial/endotype state, and spatial inflammatory niche, guided by fluid, imaging, and omics biomarkers. Future therapies should selectively suppress harmful immune responses while preserving beneficial glial functions.
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BibTeX
@article{li2026rethinking,
title = {{Rethinking Anti-Inflammatory Therapy in Alzheimer’s Disease: From Broad Suppression to Stage–State–Space Neuroimmune Reprogramming}},
author = {Xiaopu Li and Xingyu Wang and Jiaxing Dou and Jiahui Wang and Feng Xue},
journal = {Cells},
year = {2026},
month = jul,
doi = {10.3390/cells15131208},
url = {https://doi.org/10.3390/cells15131208},
note = {CC BY},
}
RIS
TY - JOUR
TI - Rethinking Anti-Inflammatory Therapy in Alzheimer’s Disease: From Broad Suppression to Stage–State–Space Neuroimmune Reprogramming
AU - Xiaopu Li
AU - Xingyu Wang
AU - Jiaxing Dou
AU - Jiahui Wang
AU - Feng Xue
PY - 2026
DA - 2026/07/02
JO - Cells
DO - 10.3390/cells15131208
UR - https://doi.org/10.3390/cells15131208
AB - Alzheimer's Disease (AD) is now understood as a biologically diverse condition, with amyloid and tau pathology evolving within dynamic neuroimmune networks. This challenges the traditional view that AD-related inflammation can be broadly suppressed therapeutically. We review evidence showing that neuroinflammation in AD is stage-dependent, cell-state-specific, spatially organized, and functionally complex. Microglia and astrocytes can aid in plaque containment, debris clearance, synaptic balance, metabolic adaptation, and tissue repair, but may also exacerbate injury through type-I interferon, inflammasome, complement, tumor necrosis factor, and lipid pathways. Many failed anti-inflammatory trials likely stem from mismatches in targets, timing, spatial considerations, pathway redundancy, and biomarker selection, rather than invalidating neuroinflammation as a therapeutic target. Recent single-cell and spatial transcriptomic, proteomic, metabolomic, and network-medicine studies offer a framework for precision intervention by identifying inflammatory endotypes, anatomical niches, and pathway modules. We propose the Stage-State-Space Neuroimmune Reprogramming Model (S3-NRM), aligning AD immunotherapy with disease stage, glial/endotype state, and spatial inflammatory niche, guided by fluid, imaging, and omics biomarkers. Future therapies should selectively suppress harmful immune responses while preserving beneficial glial functions.
SN - 2073-4409
ER -