Accumulating evidence suggests that alpha-synuclein plays a role in the pathophysiology of Alzheimer's disease (AD). This study examined whether alpha-synuclein level in cerebrospinal fluid (CSF) was associated with cognitive functioning among older adults. We also explored whether this relationship was mediated by proinflammatory cytokines TNF-alpha and IL-6, along with sIL-6R and vascular endothelial growth factor (VEGF).Using a cross-sectional Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 148) sample, we examined the relationship between alpha-synuclein and participants' performance on Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog 13) at baseline. Mediation analyses were utilized, adjusting for age, education, APOEe4, and Geriatric Depression Scale scores. All biological markers were measured in CSF. Participants in the current sample were 58.3% males, 41.7% females, and Caucasian (95.5%); their average education and age were 15.5 (standard deviation [SD] = 2.97) and 74.4 (SD = 7.51) years, respectively. Higher accumulation of alpha-synuclein was associated with poorer MMSE scores (beta = -0.41, standard error [SE] = 1.54, p < .001). This relationship appeared to be mediated by VEGF (beta = 0.27, SE = 2.15, p = .025) and IL-6r (beta = 0.22, SE = 1.66, p < .026). In addition, alpha-synuclein was associated with poorer performance on the ADAS-Cog 13 (beta = 0.34, p = .005) and mediated by VEGF (beta = -0.19, SE = 4.13, p = .025) after adjusting for age, education, APOEe4, and depressive symptoms. alpha-Synuclein may serve as an additional biomarker for determining poor cognitive functioning. VEGF and IL-6 soluble receptors were significant mediators of the relationship between alpha-synuclein and cognitive functioning. If confirmed in prospective analyses, these findings can further inform the pathologic cascade and early diagnosis of AD
