There is good epidemiological evidence that vascular disease predisposes to cognitive decline and dementia.
The impact of vascular disease on dementia is likely to increase further because of the poor diagnosis and management of
vascular risk factors, the increase in life expectancy, and the improved survival following major cardiovascular events,
e.g. acute stroke. It is estimated that the adequate management of vascular risk factors, with pharmacological and/or nonpharmacological
interventions, might result in a 50% reduction in the forecasted dementia prevalence. The exact mechanisms
by which vascular risk factors and vascular disease adversely affect brain function remain unclear, but it is hypothesized
that endothelial dysfunction plays an important role. Reduced synthesis and availability of endothelial nitric oxide
(NO) may contribute to the development of dementia by at least two mechanisms: 1) favoring the onset and progression of
atherosclerosis, vasoconstriction, and impaired cerebral blood flow regulation; and 2) reduced neuroprotection.
Several studies have shown that asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino
acid L-arginine, inhibits NO synthesis and favors oxidative stress and vascular damage. Unlike NO, ADMA concentrations
are relatively stable and can be accurately measured in plasma. There is good evidence that higher plasma ADMA
concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in
several patient groups. ADMA might represent a unifying pathophysiological pathway linking the presence of vascular
risk factors with the onset and progression of cognitive decline and dementia. This review discusses the biological role of
ADMA, its potential contribution to the onset and progression of dementia through vascular disease and atherosclerosis,
the available evidence linking ADMA with cognitive impairment and dementia, and the strategies to characterize the predictive
role of ADMA in cognitive impairment in epidemiological studies. Therapeutic implications and suggestions for
future research directions are also discussed.