Alzheimer’s disease (AD) is the leading cause of dementia worldwide; we still have no cure. Plaques of amyloid proteins and neurofibrillary tangles of tau proteins are the two hallmarks of AD. The last decades of research have mainly focused on amyloid, with limited success in clinical trials to date. It is also increasingly clear that the causes and manifestations of the disease are multifactorial. There is thus a crucial need to develop new therapeutic avenues, along with identifying robust markers that can track disease progression. The proposed project will characterize the clinical, anatomical and molecular heterogeneity of tau pathology to help identify novel drug targets and better predict individual disease trajectories. It will build upon a large, longitudinal, well-characterized cohort, ranging from preclinical older adults to dementia patients, for which the latest technical research advances are available. Using the latest positron emission tomography ligand to image tau directly in the brain, we will group participants according to their pattern of tau deposition to form different subtypes. We then will study in great detail which brain and molecular mechanisms underlie the accumulation of pathology and cognitive decline in the different tau subtypes. Characterizing the multifactorial markers underlying tau pathology will clarify mechanisms of AD pathogenesis to improve future treatment development and disease prognosis.