BackgroundAutosomal dominant Alzheimer's disease (ADAD) offers a distinct framework to study the preclinical phase of Alzheimer's disease (AD), due to its predictable symptom onset and high penetrance of causative mutations. The study aims to examine the spatial distribution and temporal progression of amyloid-beta (A beta) and tau pathologies, along with mapping the pathology-functional connectivity network, in asymptomatic ADAD mutation carriers using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI).MethodsParticipants were recruited from the Chinese Familial Alzheimer's Disease Network, comprising 14 asymptomatic ADAD mutation carriers and 20 cognitively normal healthy controls (CN). A beta deposition was evaluated using 11C-PIB PET, while tau aggregation was assessed via 18F-MK6240 PET imaging. Resting-state functional connectivity (rsFC) was analyzed to investigate relationships between pathological burden and neural network changes. Through qualitative analysis, ADAD carriers with marked 18F-MK6240 uptake in intracranial regions were categorized into Group 2, while others were designated as Group 1.ResultsAsymptomatic ADAD carriers demonstrated a significantly greater A beta burden across the cortex and striatum compared to CN, although tau PET binding did not differ significantly between the groups. Group 2 participants exhibited elevated 11C-PIB uptake in the neocortex and striatum, and increased 18F-MK6240-PET uptake in the medial temporal and other cortical regions. Compared with Group 1, network mapping of rsFC in Group 2 indicated increased connectivity associated with tau deposition in limbic, posterior cortical, and bilateral temporal regions, overlapping with the default mode network, suggesting potential compensatory mechanisms. Additionally, reduced connectivity in the left medial inferior temporal cortex and fusiform gyrus aligned with findings in sporadic AD cases.ConclusionsThis study shows the spatiotemporal progression of A beta and tau pathologies in preclinical ADAD, supporting the hypothesis that A beta deposition precedes tau pathology. The rsFC alterations observed associate with tau deposition in asymptomatic carriers indicate early network disruptions. Tau network mapping presents a valuable approach for assessing individualized brain connectivity changes in preclinical AD, mitigating single-subject variability and advancing precision assessment in early-stage AD diagnosis.