Abstract Tau pathology in Alzheimer disease (AD) is often evaluated in regions associated with episodic memory impairment. However, heterogeneous spreading patterns of tau are observed and correspond to impairment in different cognitive domains. We have previously developed a metric to quantify tau spread extent that is robustly sensitive to atypical spreading patterns. Here, we evaluate tau spread relative to domain-specific and general cognitive impairments during early stages of AD. 529 participants with baseline tau positron emission tomography (PET) and neuropsychological testing were separated into disease stage groups based on amyloid PET positivity and clinical status via CDR. General cognition was assessed using the Knight Preclinical Alzheimer Cognitive Composite (Knight PACC). Domain-specific composites were calculated for episodic memory, semantic memory, working memory, and attention/processing speed. Baseline tau burden, the average tau intensity across previously defined AD signature regions, and baseline tau spread extent, the proportion of the brain with elevated tau pathology, were quantified for each participant as Tau Index and Tau Spatial Spread respectively. Tau burden and tau spread were evaluated relative to baseline and longitudinal cognitive performance, as well as longitudinal clinical progression. Tau burden and tau spread extent both significantly correlate with cognitive impairment in symptomatic AD. Tau burden is most strongly correlated to episodic (r = -0.37, p = 0.02) and semantic (r = -0.36, p = 0.02) memory. In contrast, tau spread extent is most strongly correlated to the Knight PACC (r = -0.37, p = 0.01) and attention/processing speed (r = -0.44, p &amp;lt; 0.01), especially in preclinical AD (r = -0.27, p &amp;lt; 0.01). Tau burden captures more variance than tau spread extent in longitudinal change in the Knight PACC, episodic memory, semantic memory, attention/processing speed, and clinical progression. Tau burden strongly relates to baseline episodic and semantic memory, which may reflect that it is heavily weighted by entorhinal tau, a region previously linked to memory processing. In contrast, stronger associations between tau spread extent and baseline attention/processing speed could reflect the inclusion of additional brain regions, particularly the frontal lobe, which support a wider range of cognitive processing. Additionally, tau spread extent is generally more sensitive to baseline preclinical deficits, however tau burden better estimates future decline across all cognitive domains and clinical symptom onset. Together, these findings suggest complementary utility of evaluating both tau burden and tau spread extent in early AD progression.

Domain-specific cognitive impairment is differentially affected by Alzheimer disease tau pathologic burden and spread