The Mediating Role of Inflammation in the Relationship Between α-Synuclein and Cognitive Functioning

Sanaz Dabiri; Mara I Ramírez Ruiz; Girardin Jean-Louis; Oyonumo E Ntekim; Thomas O Obisesan; Alfonso L Campbell; Denée T Mwendwa; Alzheimer’s Disease Neuroimaging Initiative

doi:10.1093/gerona/glac217

The Mediating Role of Inflammation in the Relationship Between α-Synuclein and Cognitive Functioning

J Gerontol A Biol Sci Med Sci. 2023 Feb 24;78(2):206-212. doi: 10.1093/gerona/glac217.

Authors

Sanaz Dabiri¹, Mara I Ramírez Ruiz¹, Girardin Jean-Louis², Oyonumo E Ntekim³, Thomas O Obisesan⁴, Alfonso L Campbell¹, Denée T Mwendwa¹; Alzheimer’s Disease Neuroimaging Initiative

Affiliations

¹ Department of Psychology, Howard University, Washington, District of Columbia, Washington, DC, USA.
² Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA.
³ Department of Graduate Nutritional Sciences, Howard University, Washington, District of Columbia, Washington, DC, USA.
⁴ Division of Geriatrics, Department of Medicine, Howard University Hospital, Washington, District of Columbia, Washington, DC, USA.

Abstract

Accumulating evidence suggests that α-synuclein plays a role in the pathophysiology of Alzheimer's disease (AD). This study examined whether α-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-α 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 α-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 α-synuclein was associated with poorer MMSE scores (β = -0.41, standard error [SE] = 1.54, p < .001). This relationship appeared to be mediated by VEGF (β = 0.27, SE = 2.15, p = .025) and IL-6r (β = 0.22, SE = 1.66, p < .026). In addition, α-synuclein was associated with poorer performance on the ADAS-Cog 13 (β = 0.34, p = .005) and mediated by VEGF (β = -0.19, SE = 4.13, p = .025) after adjusting for age, education, APOEe4, and depressive symptoms. α-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 α-synuclein and cognitive functioning. If confirmed in prospective analyses, these findings can further inform the pathologic cascade and early diagnosis of AD.

Keywords: Alzheimer’s disease; Biomarker; Cognitive decline; Immune response; α-Synuclein.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Alzheimer Disease* / diagnosis
Biomarkers / cerebrospinal fluid
Cognition
Cognitive Dysfunction* / diagnosis
Cross-Sectional Studies
Female
Humans
Inflammation
Interleukin-6
Male
Neuropsychological Tests
Prospective Studies
Vascular Endothelial Growth Factor A
alpha-Synuclein / cerebrospinal fluid

Substances

alpha-Synuclein
Vascular Endothelial Growth Factor A
Interleukin-6
Biomarkers

Grants and funding

U01 AG024904/AG/NIA NIH HHS/United States