Neurovascular Mechanisms in Alzheimer's Disease

Alzheimer’s disease is increasingly recognised as a disorder arising from intertwined neural and vascular dysfunctions rather than purely neuronal degeneration. The neurovascular unit, composed of endothelial cells, pericytes, astrocytes and neurons, orchestrates cerebral blood flow, nutrient exchange and barrier integrity. In Alzheimer’s, amyloid-β accumulation, tau hyperphosphorylation and ApoE genotype influence vascular permeability and reduce capillary perfusion. Early vascular alterations including basement membrane thickening, pericyte loss and aberrant angiogenesis impede clearance of toxic proteins and provoke chronic inflammation. Leakage of blood proteins such as fibrinogen and monomeric C-reactive protein into the parenchyma activates microglia, which release oxidative and inflammatory mediators that exacerbate endothelial injury. Regionally selective hypoperfusion in structures such as the precuneus and hippocampus correlates with cognitive decline, highlighting the diagnostic value of imaging of blood–brain barrier integrity and flow dynamics. A deeper mechanistic understanding of neurovascular interactions offers novel biomarkers and therapeutic targets aimed at restoring vascular resilience and slowing disease progression.

Research from Nature Portfolio

Recent studies have employed unbiased multi-omic pipelines to dissect the impact of blood protein extravasation on innate immune cells in Alzheimer’s models. Introduction of fibrinogen into the brain milieu was shown to drive distinct microglial transcriptional and phosphoproteomic signatures linked to redox stress, interferon pathways and lipid metabolism. Genetic ablation of the fibrinogen-CD11b interaction ameliorated these neurodegenerative profiles, pointing to potential immunovascular therapeutic strategies.

Investigations into monomeric C-reactive protein (mCRP) have uncovered its role in bridging cerebrovascular ischaemia and Alzheimer’s pathology. Direct mCRP deposition in mouse hippocampus induced tau phosphorylation, amyloid-β aggregation and angiogenic vessel changes, accompanied by endothelial signalling through ERK1/2 and increased vascular permeability. Post-mortem analyses of stroke and Alzheimer’s patients confirmed colocalisation of mCRP with plaques and tau fibrils, underscoring its potential as a mediator of inflammatory vascular damage.

Neurovascular Mechanisms in Alzheimer's Disease publication trend

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

Technical terms

Neurovascular unit (NVU): A functional complex of endothelial cells, pericytes, astrocytes and neurons that regulates cerebral blood flow and barrier integrity.

Blood–brain barrier (BBB): The selective endothelial interface that restricts passage of substances from the blood to the brain.

Monomeric C-reactive protein (mCRP): A pro-inflammatory form of C-reactive protein that accumulates in ischaemic tissue and can affect vascular cells.

Fibrinogen: A blood coagulation protein that can infiltrate the brain after barrier breakdown and trigger microglial activation.

Vascular endothelial growth factor (VEGF): A signalling molecule that drives angiogenesis and regulates vascular permeability.

Amyloid-β: A peptide that aggregates into plaques and disrupts neuronal and vascular function in Alzheimer’s disease.

Tau: A microtubule-associated protein that forms neurofibrillary tangles and can induce vascular abnormalities.

References

1. Defining blood-induced microglia functions in neurodegeneration through multiomic profiling. Nature Immunology (2023).
2. Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer’s disease. Translational Neurodegeneration (2024).
3. Tipping points in neurodegeneration. Neuron (2023).
4. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America (2018).
5. Monomeric C-reactive protein-a key molecule driving development of Alzheimer’s disease associated with brain ischaemia?. Scientific Reports (2015).