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Cerebral Small Vessel Disease in Sporadic and Familial Alzheimer Disease

Lookup NU author(s): Professor Raj Kalaria



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021 American Society for Investigative PathologyAlzheimer disease (AD) is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary pathology, and neurodegeneration. However, current evidence suggests that various features of small vessel disease (SVD) are part of and covertly modify both sporadic and familial AD. Neuroimaging studies suggest that white matter hyperintensities explained by vascular mechanisms occurs frequently in the AD spectrum. Recent advances have further emphasized that frontal periventricular and posterior white matter hyperintensities are associated with cerebral amyloid angiopathy in familial AD. Although whether SVD markers precede the classically recognized biomarkers of disease is debatable, post-mortem studies show that SVD pathology incorporating small cortical and subcortical infarcts, microinfarcts, microbleeds, perivascular spacing, and white matter attenuation is commonly found in sporadic as well as in mutation carriers with confirmed familial AD. Age-related cerebral vessel pathologies such as arteriolosclerosis and cerebral amyloid angiopathy modify progression or worsen risk by shifting the threshold for cognitive impairment and AD dementia. The incorporation of SVD as a biomarker is warranted in the biological definition of AD. Therapeutic interventions directly reducing the burden of brain amyloid β have had no major impact on the disease or delaying cognitive deterioration, but lowering the risk of vascular disease seems the only rational approach to tackle both early- and late-onset AD dementia.

Publication metadata

Author(s): Kalaria RN, Sepulveda-Falla D

Publication type: Review

Publication status: Published

Journal: American Journal of Pathology

Year: 2021

Volume: 191

Issue: 11

Pages: 1888-1905

Print publication date: 01/11/2021

Online publication date: 28/07/2021

Acceptance date: 02/07/2021

ISSN (print): 0002-9440

ISSN (electronic): 1525-2191

Publisher: Elsevier Inc.


DOI: 10.1016/j.ajpath.2021.07.004

PubMed id: 34331941