PET radiotracers targeting amyloid beta (Aβ) plaques and hyperphosphorylated tau, the two major hallmarks of Alzheimer’s disease (AD), have been instrumental in clinical and research settings to study AD and related dementia. However, strong evidence indicate the involvement of multiple pathological processes in AD, including demyelination and vascular dysfunction, that may be coexisting with and could even precede Aβ and tau neuropathologies. Demyelination has been traditionnally imaged with magnetic resonance imaging (MRI). MR sequences offer good spatial resolution and sensitivity toward demyelinated areas in the white matter (WM) but lacks specificity, quantitative value and sensitivity toward gray matter (GM) demyelination. In order to adress these limitations, [18F]3F4AP was recently developed to provide specific and quantitative measurements of demyelination with PET. [18F]3F4AP binds to voltage-gated potassium (Kv) channels which are exposed and increase in expression upon demyelination, thus serving as an indirect biomarker for demyelination. This compound demonstrated excellent imaging properties with good sensitivity toward demyelinated lesions in preclinical studies and, more recently, was able to detect lesions in human subjects with multiple sclerosis (MS). In addition, [18F]3F4AP shows high brain permeability, suggesting that, in addition to measuring demyelination, this radiotracer could also provide quantitative measurements of cerebral perfusion. In this application, we propose to characterize [18F]3F4AP’s properties and performance for detecting and quantifying demyelination and cerebral perfusion in subjects with AD, mild cognitive impairment (MCI), and cognitively normal (CN) individuals. We will perform the first full pharmacokinetic evaluation of this tracer in human subjects with AD and subjects with MCI and we will validate simplified imaging protocols and quantification methods towards clinical translation. We will also assess associations between quantitative measures of demyelination, CBF, Aβ plaques and tau load.