Gray matter hypoperfusion is a late pathological event in the course of Alzheimer's disease.

ABSTRACT

Several studies have shown decreased cerebral blood flow (CBF) in Alzheimer's disease (AD). However, the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, PET, and CSF biomarkers, we investigated the associations between gray matter (GM)-CBF and the key mechanisms in AD including amyloid-ß (Aß) and tau pathology, synaptic and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in temporo-occipito-parietal cortex in the Aß-positive cognitively impaired compared to both Aß-negative and Aß-positive cognitively unimpaired individuals. In participants along the AD spectrum, GM-CBF was associated with tau, synaptic and axonal dysfunction, but not Aß in similar cortical regions. Axonal degeneration was further associated with hypoperfusion in cognitively unimpaired individuals. Disease progression modeling revealed that GM-CBF disruption Followed the abnormality of biomarkers of Aß, tau and brain atrophy. These findings indicate that tau tangles and neurodegeneration are more closely connected with GM-CBF changes than Aß pathology. Although subjected to the sensitivity of the employed neuroimaging techniques and the modeling approach, these findings suggest that hypoperfusion might not be an early event associated with the build-up of Aß in preclinical phase of AD.