Immune System Dynamics in Alzheimer's Disease

Alzheimer’s disease is increasingly recognised as a disorder in which the immune system plays a central, dynamic role. Within the brain, resident microglia and astrocytes respond to amyloid-β deposits and tau aggregates by adopting pro-inflammatory or reparative states. At the same time, peripheral immune cells—including T lymphocytes, B lymphocytes and monocytes—can infiltrate the central nervous system (CNS), influencing plaque clearance, synaptic integrity and neuronal survival. Systemic factors such as metabolic stress or obesity further modulate these interactions by altering cytokine profiles and inducing immune exhaustion. Together, innate and adaptive components orchestrate a complex neuroimmune axis that affects disease onset, progression and response to therapy. Understanding these bidirectional pathways offers routes to novel immunomodulatory strategies, from antigen-specific regulatory T cell therapies to targeted depletion of B cells, with the potential to slow cognitive decline and restore homeostasis in patients worldwide.

Research from Nature Portfolio

Recent studies have identified metabolic and cellular drivers of immune dysfunction in Alzheimer’s models. One investigation revealed that excess N-acetylneuraminic acid, derived from obesogenic diets, directly impairs CD4+ T cell proliferation and accelerates memory deficits, linking systemic metabolism to splenic immune exhaustion and hippocampal dysfunction. In parallel, work on regulatory T cells has demonstrated that transient depletion of Foxp3+ cells alleviates amyloid burden, mitigates neuroinflammation and restores cognitive performance by enhancing recruitment of reparative myeloid populations across the choroid plexus. More recently, targeted removal of B cells in transgenic mice was shown to reduce plaque deposition, normalise microglial phenotypes and reverse behavioural deficits, suggesting that peripheral B-cell activity sustains disease pathology and may be amenable to antibody-mediated intervention.

Immune System Dynamics in Alzheimer's Disease publication trend

The graph below shows the total number of articles in immune system dynamics in alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Microglia: Resident immune cells of the CNS that clear debris and modulate inflammation.

Regulatory T cells (Tregs): A subset of adaptive lymphocytes that suppress excessive immune responses.

Amyloid-β (Aβ): A peptide that aggregates into plaques and drives neuroinflammation and toxicity.

Cytokine: A signalling protein, such as interleukin-17, that mediates immune cell communication.

Blood–brain barrier (BBB): A selective vascular interface that normally restricts immune cell entry into the brain.

Adaptive immunity: The branch of the immune system involving antigen-specific T and B lymphocytes.

References

1. Amyloid-β specific regulatory T cells attenuate Alzheimer’s disease pathobiology in APP/PS1 mice. Molecular Neurodegeneration (2023).
2. N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model. Nature Communications (2023).
3. The neuroimmune axis of Alzheimer’s disease. Genome Medicine (2023).
4. Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology. Nature Communications (2015).
5. IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer’s disease. Cell Reports (2021).
6. Therapeutic B-cell depletion reverses progression of Alzheimer’s disease. Nature Communications (2021).
7. Single-Cell RNA Sequencing of Peripheral Blood Reveals Immune Cell Signatures in Alzheimer’s Disease. Frontiers in Immunology (2021).