Biomarkers

Background: Little is known about how plasma Alzheimer's disease (AD) biomarkers relate to neuroimaging biomarkers of cerebral small vessel disease (cSVD) in the context of neurodegeneration and AD pathology in late life.

Method: This cross-sectional study included 251 Multi-Ethnic Study of Atherosclerosis (MESA) Exam 6 participants with plasma AD biomarkers (Aβ42/Aβ40, GFAP, NfL, p-tau181, p-tau217, p-tau231; Quanterix SIMOA), MRI (neurodegeneration and cSVD), PiB (amyloid) PET, and UDSv3-based adjudicated cognitive status (69% cognitively normal, 27% MCI, 4% probable dementia) data at the Wake Forest site. Multivariable models examined relationships among cognitive status, plasma, and neuroimaging biomarkers (covariates: age, education, race, gender, smoking status, kidney function [eGFR], APOE-ε4, BMI; significance at p<.05 uncorrected).

Result: Cognitive status associated with imaging biomarkers and with plasma biomarkers of Aβ42/Aβ40, GFAP, p-tau217 and p-tau231. No NfL or p-tau181 group differences were observed (Table 1). Lower plasma Aβ42/Aβ40 (Table 2) was associated with lower gray matter (GM) volume (GMV) and hippocampal volume (HCV); higher GFAP levels were associated with lower HCV. Higher NfL levels were associated with lower GMV and HCV, and with higher GM Free Water (FW). Higher p-tau217 levels were associated with lower GMV. Plasma p-tau231 was not associated with neurodegeneration imaging biomarkers. Higher NfL levels were associated with higher white matter (WM) hyperintensity (WMH) volume and WM FW. All plasma tau measurements were positively associated with WM FW but not other cSVD biomarkers. Lower Aβ42/Aβ40 ratio was significantly associated with greater prevalence of microbleeds. Higher GFAP was associated with higher WMH volume. As anticipated, lower plasma Aβ42/Aβ40 ratio and higher p-tau217 and p-tau231 were associated with higher Aβ deposition and odds of Aβ positivity (Table 3); a doubling in the level of p-tau217 or p-tau231 was associated with a 2-3 fold increase in the odds of Aβ PET positivity.

Conclusion: We found that plasma GFAP, NfL, p-tau181, p-tau217, and to a lesser extent p-tau231 are associated with cognitive status, vascular comorbidities and imaging biomarkers of cSVD, in addition to measures of AD-related pathology. Importantly, we demonstrated novel associations between plasma AD biomarkers of p-tau and NfL with cSVD measures of WM structural health.