Aims

Amyloid beta 1-40 (Aβ40) in CSF is a promising biomarker for cerebral amyloid angiopathy (CAA)¹. Here we assess the mediating effect of CSF Aβ40 on the increase in global and regional white matter hyperintensities (WMHs) in early-stage sporadic Alzheimer’s disease (AD).

Methods

221 controls and cases with subjective cognitive decline or mild cognitive impairment were included from the longitudinal Norwegian Dementia Disease Initiation (DDI) multi-site study. We stratified on CSF Aβ42 pathology (Aβ42+/-), using an amyloid-PET verified cutoff. Global and regional WMH volumes on FLAIR MRI were determined using a novel automated algorithm, and were normalized to global or regional brain volumes, respectively. Mediation analysis was performed to find the indirect effect of CSF Aβ40 on the association between Aβ42 status and WMHs, correcting for age, sex, pulse pressure and scanners.

Results

We found that 23% of the increase in global WMHs and 17-33 % of the increase in regional WMHs in Aβ42+ individuals was mediated by CSF Aβ40 levels, with the largest indirect effect in the occipital lobe. There were significant direct effects of Aβ42+ status on global, parietal and temporal WMH loads.

Conclusions

These results suggest that increased WMH load in early-stage sporadic AD is partially mediated by CAA, but also support the hypothesis that WMHs are a core feature in AD.

1. Van Etten ES et al. β-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy. Neurology 2017