Immune Dysfunction in Alzheimer’s Disease — Our Latest Review in Nature Reviews Neuroscience

In November 2025, our review “Immune dysfunction in Alzheimer’s disease” was published in Nature Reviews Neuroscience, where we synthesize the rapidly evolving understanding of how immunity contributes to Alzheimer’s disease (AD). This work brings together conceptual, mechanistic, and translational perspectives to outline how both peripheral and central immune pathways shape disease initiation and progression.

I contributed to the conceptual development, manuscript formulation, writing, and the design and creation of several figures in the review, working closely with colleagues across neuroimmunology, genetics, and systems neuroscience.

The Immune System as a Driver of Alzheimer’s Disease

Alzheimer’s disease has long been understood through the lens of amyloid and tau pathology, yet these hallmarks interact deeply with the immune system. Our review highlights how:

microglia integrate genetic risk with environmental and aging cues
astrocytes, oligodendrocytes, and peripheral immune cells participate in maladaptive inflammatory loops
T cells, cytokine environments, and innate immune sensors contribute to chronic neuroinflammation
systemic immune aging reshapes brain homeostasis long before cognitive symptoms appear

Rather than treating immunity as a downstream response, we argue that immune dysfunction actively shapes the trajectory of the disease.

Key Concepts from the Review

Genetic Risk Converges on Microglia

Genes like TREM2, CD33, and APOE4 point toward microglial dysfunction as a core disease mechanism. Many of these risk alleles regulate lipid handling, phagocytosis, nucleic acid sensing, and inflammatory signaling.

Transposable Elements and Nucleic Acid Sensing

A major conceptual theme is the recognition that endogenous nucleic acids—including those derived from transposable elements—can activate innate immune pathways. These interactions may contribute to chronic interferon signaling, synaptic dysfunction, and microglial state transitions in AD.

Peripheral Immunity Matters

Growing evidence suggests that peripheral immune cells infiltrate the brain or influence neuroinflammation from the periphery. Dysregulation of monocytes, T cells, and inflammatory cytokines increasingly appears to be part of the disease cascade.

Microglial State Dynamics

We summarize emerging microglial subpopulations—including disease-associated microglia (DAM), interferon-response microglia (IRM/IEM), and lipid-associated states—that link molecular profiles to pathological stages.

Figures: Clarifying Complexity Through Visual Integration

To help readers navigate this complex landscape, our review includes several integrative figures summarizing:

the temporal evolution of immune dysfunction
interactions between microglia, peripheral immune cells, and pathological proteins
molecular pathways linking transposable elements, nucleic acid sensing, and interferon responses
therapeutic strategies targeting immune pathways

I designed and produced these figure panels to distill multi-layered findings into accessible visual overviews.

Looking Ahead: Immune Pathways as Therapeutic Gateways

A key message of our review is that immune dysfunction is not merely a consequence of AD—it is a modifiable driver. Future interventions may target:

microglial checkpoints
interferon signaling
TREM2 and lipid metabolism pathways
peripheral immune modulation
nucleic acid sensing and inflammation triggered by transposable elements

Understanding these mechanisms offers a roadmap for next-generation therapies that intervene earlier and more precisely.

Read the Full Article

You can read the full review here:
https://www.nature.com/articles/s41583-025-00997-0