DS is considered a condition with a low risk of clinical atherosclerosis and cardiovascular disease during adult and later life. An increment of molecules with functional roles in endothelial cell activation should raise the risk of atherosclerosis in DS. However, since DS is considered an atheroma-free model [
2] and clinical investigations do not report any rise in the risk of cardiovascular disease in adult and elderly patients, DS patients constitute a still unsolved biological/clinical paradox [
4]. Questions remain about the role of BDNF in atherosclerosis. We do not know why the level BDNF appears to be significantly depleted in humans with coronary atherosclerosis [
10,
11]. The fact that plasma BDNF levels are significantly reduced in the chronic, advanced [
3] and acute stages [
10] of coronary atherosclerosis points to a potential role of a deficit of this neurotrophin in atherosclerosis pathogenesis [
12]. Neurotrophins are potentially important in atherosclerosis and related disorders [
3,
5]. A significant decrease in plasma NGF and BDNF was associated with the metabolic syndrome and atherosclerosis [
13]. Age-related neurodegeneration associated with AD correlates with changes in BDNF expression too [
8]. Recent investigations have looked into the hypothesis of a possible diurnal variation of BDNF circulating levels in human males. A correlation with cortisol circadian rhythm has also been sought, since both BDNF and cortisol are implicated in the maintenance of cerebral functions [
14]. It has been suggested that BDNF might stimulate the production of proteins involved in cellular stress adaptation, growth and repair, neurogenesis, learning and memory and cell survival. There is also evidence that an increase of BDNF in either plasma or tissue has therapeutic potential [
13]. Taking into account that BDNF is required for survival and function of hippocampal, cortical, basal forebrain, and entorhinal cortex neurons, and that in DS the neuropathological aspects are complex and include development of Alzheimer's disease (AD) in older age, we wanted to evaluate the change in BDNF levels in different age groups of Down's Syndrome patients, compared to the same age range healthy controls. Here we show an age-related increase of BDNF level DS patients serum, thus indicating a protective role of this molecule against atherosclerosis risk as observed by Nelson at al [
15], showing that BDNF increase with age in healthy subject. Our data confirmed this age related increase in healthy control subjects, even if not statistically significative, and moreover it pointed out that this BDNF level increase is significatively higher in DS patients, in particular in old ones. In addition, among DS patients, this increase fits with an age related and progressive decrease of the proinflammatory and atherogenic cytokines IL-6 and MCP-1. Here we showed that plasma IL-6 and MCP-1 levels were elevated in DS compared to control subject, further supporting the notion of vessel dysfunction. This elevated level could not be ascribed to clinical inflammation, since DS patients had no clinically detectable pathological conditions. Therefore, it is likely that the plasma high level of pro-inflammatory cytokines in DS patients is due to endothelial activation without activation of immune responses. Elevated levels of IL-6 and intercellular adhesion molecules have been associated with endothelial dysfunction in various pathological conditions, such as atherosclerosis and its complications [
9]. However, our results indicate that these elevated serum levels of the pro-inflammatory and atherogenic cytokines IL-6 and MCP-1 in DS patients, progressively decrease with age, in parallel with an age related increase of BDNF level.