Biomarkers

Reduced cerebral perfusion is a common pathological alteration in mild cognitive impairment and dementia[1]. Lower grey matter(GM) perfusion is predictive of cognitive decline[2] and conversion from mild cognitive impairment to dementia[3]. Thus, quantification of GM perfusion can be an important candidate biomarker of dementia risk[4]. Additionally, Aβ1-40 as well as neuroinflammation have also been shown to play a significant role in vascular aging[5]. However, the link between CBF alterations and primary pathologies including Aβ1-40 and fibrillar tau remains unclear. To address this gap, we sought to examine the impact of plasma Aβ, phosphorylated-tau 181 (p-tau181) and age on cerebral perfusion through pathways involving white matter hyperintensities burden (WMH) and the neuroinflammation marker, glial fibrillary acidic protein (GFAP).

Study participants belonged to the community-based Biomarker and Cognition Cohort Study in Singapore and underwent cross-sectional structural(T1)-functional (Arterial spin labelling perfusion) MRI. Plasma-based SIMOA assessment of p-tau181, Aβ1-40 and GFAP was carried out. Path analyses was constructed using RStudio lavaan package. Key predictors included p-tau181, Aβ1-40, age-at-visit with global grey matter cerebral perfusion as the main outcome variable. Log-transformed WMH volume and plasma GFAP were included as mediators. Direct and indirect paths were defined. Missing values were imputed using mean imputation.

729 participants (mean age 62.8 years; 59.3% female sex) were included. Path analysis demonstrated a good model fit with a comparative fit index of 0.986 and Standardized Root Mean Square Residual of 0.014. Significant paths revealed p-tau181 and age-at-visit being strong predictors of both GFAP and WMH, with logWMH negatively affecting GM perfusion. Aβ1-40 was also a positive predictor of GFAP. Notably, the indirect effect of p-tau181 on GM perfusion through logWMH was significant and negative. There were no indirect effects of p-tau181 on GM perfusion through GFAP. There were also no indirect effects of Aβ1-40 on GM perfusion through GFAP or WMH.

This study attempts to examine simultaneous direct and indirect causal pathways between Aβ1-40, p-tau181 and age-at-visit on GM perfusion through GFAP and WMH. Our finding of indirect effect of p-tau181 on GM hypoperfusion suggests a causal downstream effect of elevated p-tau181 resulting in reduced GM perfusion through WMH.