Investigating the Aβ and tau pathology in autosomal dominant Alzheimer’s disease: insights from hybrid PET/MRI and network mapping

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Autosomal 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 (Aβ) 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). Participants were recruited from the Chinese Familial Alzheimer’s Disease Network, comprising 14 asymptomatic ADAD mutation carriers and 20 cognitively normal healthy controls (CN). Aβ deposition was evaluated using 11 C-PIB PET, while tau aggregation was assessed via 18 F-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 18 F-MK6240 uptake in intracranial regions were categorized into Group 2, while others were designated as Group 1. Asymptomatic ADAD carriers demonstrated a significantly greater Aβ 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 11 C-PIB uptake in the neocortex and striatum, and increased 18 F-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. This study shows the spatiotemporal progression of Aβ and tau pathologies in preclinical ADAD, supporting the hypothesis that Aβ 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.

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