The vascular contribution to dementia: World Stroke Organization scientific statement

Alzheimer's disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50-70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes.

In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive.

We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules (COL4A1/4A2, HTRA1, TRIM47, FOXF2) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia.

The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities.Data Access Statement:no original data are presented in this document.