Abstract Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer’s disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer’s disease-characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer’s disease spectrum in comparison to those of established imaging- and fluid-derived biomarkers of Alzheimer’s disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) ( n =1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an [18F]florbetapir amyloid-β (Aβ) positron emission tomography (PET) scan at baseline. A subset of participants ( n =864) also had measures of Aβ 1-42 and p-tau181 levels in cerebrospinal fluid (CSF), and another subset ( n =298) had undergone an [18F]flortaucipir tau PET scan six years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional Aβ pathology and tau burden six years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer’s disease biomarkers employing a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Spline regressions demonstrated that earliest plasma p-tau181 changes occurred even before Aβ-markers reached abnormal levels, with greater rates of change correlating with increased Aβ pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with Aβ pathology in early-accumulating brain regions in cognitively healthy individuals, while the strongest associations with Aβ were observed in late-accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation six years later, covering temporo-parietal regions typical for neurofibrillary tangle distribution in Alzheimer’s disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels approximately 6.5 and 5.7 years after CSF- and PET-measures of Aβ, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical Aβ pathology and with prospective Alzheimer’s disease-typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer’s disease.