INTRODUCTION: The spatial heterogeneity of tau deposition is closely linked to clinical variants of Alzheimer's disease (AD). Detecting these patterns in the preclinical stage is challenging, but second-generation tau tracers provide a unique opportunity to do so.

METHODS: We used independent component analysis (ICA) and tau positron emission tomography (PET) imaging with the 18F-MK6240 tracer in 590 cognitively healthy adults (mean age 66.58 ± 5.13 years, 340 females) to identify tau patterns in the preclinical stage.

RESULTS: Using all individuals, seven distinct patterns emerged, with medial temporal lobe (MTL) involvement associated with age, Aβ burden, apolipoprotein E (APOE) genotype, and plasma total tau. Bilateral amygdala-hippocampus tau deposition was associated negatively with memory (t = -2.64, p < 0.01), while broader neocortical patterns, especially asymmetric ones, were linked to deficits in language (t < -3.13, p < 0.002) and reasoning (t < -2.63, p < 0.01).

DISCUSSION: These findings advance our understanding of preclinical tau heterogeneity, offering new insights for early AD intervention.

HIGHLIGHTS: Seven tau deposition patterns were identified in preclinical stages of AD, including medial temporal lobe and asymmetric neocortical patterns. Medial temporal lobe patterns were strongly linked to age, APOE genotype, Aβ burden, and plasma total tau levels. Neocortical patterns, especially asymmetric ones, were linked to domain-specific cognitive deficits, notably in language and reasoning. This research highlights the potential of using tau deposition patterns for early detection and tailoring interventions in preclinical AD.