Alzheimer’s disease (AD) is believed to have a prolonged preclinical phase when aggregates of soluble, neurotoxic tau and amyloid species accrue and slowly develop into positron emission tomography (PET)-detectable neurofibrillary tangles and amyloid plaques, respectively, which in turn herald the onset of mild cognitive impairment (MCI) and dementia. Hence, understanding the spatiotemporal timeline for the accrual of these early pathological species prior to PET detection and clinical symptoms will facilitate the development of disease-modifying AD therapies. In this study, we quantified the accumulation of early pre-tangle tau in postmortem tissue from medial frontal cortex, precuneus (PreC) and posterior cingulate cortex (PCC), which comprise critical hubs of the Default Mode network (DMN), a functional brain network underlying memory and attention that falters very early in AD patients. Using tissue samples from controls as well as MCI and mild AD subjects from the Rush Religious Orders Study (n=10/group), we labeled pathological tau with the pre-tangle phospho- and conformational epitope-specific antibodies pS422, TOC1, and TNT2. All four markers began to elevate in the MCI cases and reached significance in the AD cases. Interestingly, tau pathology load for the markers was tightly and inversely correlated with antemortem performance on tests of semantic memory and episodic memory, which are mediated by PreC and PCC function, as well as a global cognitive z-score of all cognitive tests taken by the subjects. These initial results shed light on early pathological tau accumulation within the DMN that might be targeted to mitigate AD progression.