ABSTRACT Recent transgenic mouse studies have highlighted impaired glymphatic function as contributing to the pathophysiology of Alzheimer's disease (AD). We learn from these studies that a reduced clearance of CSF, which carries proteins like A? and waste products, needs to be considered in the development of amyloid plaques and pathophysiology of AD. These emergent observations complement the well characterized trans- endothelial A? clearance impairments in AD. Lumbar puncture studies have confirmed an impaired clearance of labelled A? to the CSF in AD patients. However, lumbar puncture studies do not distinguish impaired trans- membrane transport of A? from impairments in CSF flow. We developed the first non-invasive technology and extended the conventional kinetic model to quantify CSF clearance. The technique uses PET to dynamically image a low molecular weight tracer with high brain penetrance, rapid clearance, and limited residual brain uptake. After controlling for blood tracer levels, our preliminary data demonstrate that ventricular (v) CSF clearance achieves 89% accuracy for the diagnosis of AD. PET estimates of vCSF clearance are highly correlated within subject across pairs of PET tracers. Our preliminary studies also revealed a previously undocumented superior nasal turbinate CSF egress pathway. Most importantly, in normal elderly (NL) CSF clearance measured at the ventricle and cingulate gyrus (a target for A? deposits) was inversely associated with the magnitude of brain A? deposits as measured by 11C-PiB PET. These observations justify our proposed longitudinal study of the relationship between CSF clearance and A? lesion progression, brain atrophy and cognitive decline. The study will enroll 90 age and gender matched PiB-positive and PiB-negative NL subjects. To avoid the confounding effect of tracer binding, we propose to use 11C-Butanol, a freely diffusible tracer we synthesized 20 years ago, with a half-life adequate for CSF measurement. In sum, this project offers the first opportunity to map CSF clearance from brain and extra-cranial sites in a test of the hypothesis that impaired CSF clearance predicts A? deposition.