Cerebral hypoperfusion is a late pathological event in the course of Alzheimer's disease

Although several studies have shown decreased cerebral blood flow (CBF) in Alzheimers disease (AD), the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, positron emission tomography, and biomarkers of cerebrospinal fluid, we investigated the associations between CBF and the key mechanisms in AD including amyloid-{beta} (A{beta}) and tau pathology, synaptic dysfunction and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in the temporo-occipito-parietal regions in the A{beta}-positive cognitively impaired compared to both the A{beta}-positive and A{beta}-negative cognitively unimpaired individuals. In participants along the AD spectrum (those with A{beta} pathology regardless of their cognitive status), CBF was inversely associated with tau and synaptic dysfunction, but not A{beta}, in similar cortical regions. Moreover, the disease progression modeling revealed that CBF disruption followed the abnormality of biomarkers of A{beta}, tau and brain atrophy. These findings indicate that tau tangles and synaptic degeneration are more closely connected with CBF changes rather than A{beta} pathology. This supports the notion that hypoperfusion is not an early event associated with the build-up of A{beta} during the preclinical phase of AD.