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The vascular contribution to cognitive decline in ageing and dementia

Nature Reviews Neuroscience volume 26, pages 591–606 (2025)Cite this article

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Abstract

There is increasing evidence to suggest that vascular dysfunction can contribute to cognitive decline in ageing and dementia. This dysfunction can take the form of a reduction of cerebral blood flow (CBF), a loss of blood–brain barrier (BBB) function or a combination of the two. Indeed, CBF and BBB changes may be causally linked, although this possible causality and its directionality are understudied. Appreciation of the role of vascular dysfunction in initiating cognitive decline in ageing and dementia, as well as the mechanisms involved, is important because it opens up new avenues for the development of much-needed therapies for these conditions, which are becoming major causes of death. Here we assess the evidence for the importance of vascular contributions to dementia, draw parallels with changes that occur in normal ageing and discuss the initiating cells and signalling mechanisms involved. We suggest that attempting to maintain or restore CBF should be a central aim of therapeutic strategies.

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Fig. 1: Mechanisms contributing to CBF decline in ageing and dementia.
Fig. 2: Pathways involved in CBF reduction in Alzheimer disease and vascular dementia.
Fig. 3: White matter hyperintensities increase in ageing and dementia, causing cognitive decline.
Fig. 4: Vascular dysfunction mechanisms and potential therapeutic approaches.

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Author information

Author notes

  1. These authors contributed equally: Silvia Anderle, Michael Dixon, Tania Quintela-Lopez, George Sideris-Lampretsas.

Authors and Affiliations

  1. BHF/UK-DRI Centre for Vascular Dementia Research, University College London, London, UK

    Silvia Anderle, Michael Dixon, Tania Quintela-Lopez, George Sideris-Lampretsas & David Attwell

  2. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    Silvia Anderle, Michael Dixon, Tania Quintela-Lopez, George Sideris-Lampretsas & David Attwell

Authors
  1. Silvia Anderle
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  2. Michael Dixon
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  3. Tania Quintela-Lopez
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  4. George Sideris-Lampretsas
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  5. David Attwell
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to David Attwell.

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The authors declare no competing interests.

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Nature Reviews Neuroscience thanks Craig Brown, Anna Csiszar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Actomyosin

The myosin and actin filaments that generate contraction within a muscle cell.

Arterioles

Larger blood vessels ringed by smooth muscle cells that feed blood to capillaries.

Capillaries

The smallest blood vessels, where nutrient and gas exchange occurs with the tissue.

Cell adhesion molecules

Molecules that join cells together, including endothelial cells.

Cerebrovascular resistance

The ratio of pressure to blood flow across a brain vascular bed.

Monocytes

An immune cell type in the blood, the largest type of white blood cell.

Neutrophils

A type of immune cell in the blood that engulfs and destroys bacteria.

Pressure autoregulation

Reflex contraction (or relaxation) of contractile cells evoked when the blood pressure rises (or falls) that tends to keep the downstream pressure constant.

Reactive oxygen species

(ROS). Reactive molecules formed by immune cells to kill bacteria or by mitochondria when energy supply is limited that can damage lipids and proteins.

Transit time

The time taken for blood to pass, for example, from the start to the end of the capillary bed.

White matter hyperintensities

White areas on magnetic resonance images of the brain that may indicate BBB leakage or fluid accumulation.

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Anderle, S., Dixon, M., Quintela-Lopez, T. et al. The vascular contribution to cognitive decline in ageing and dementia. Nat. Rev. Neurosci. 26, 591–606 (2025). https://doi.org/10.1038/s41583-025-00950-1

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