Objective: To delineate the relationship between clinical symptoms and tauopathy of the hippocampal subfields under different amyloid statuses.Methods: One hundred and forty-three subjects were obtained from the ADNI project, including 87 individuals with normal cognition, 46 with mild cognitive impairment, and 10 with Alzheimer’s disease (AD). All subjects underwent the tau PET, amyloid PET, T1W, and high-resolution T2W scans. Clinical symptoms were assessed by the Neuropsychiatric Inventory (NPI) total score and Alzheimer’s Disease Assessment Scale cognition 13 (ADAS-cog-13) total score, comprising memory and executive function scores. The hippocampal subfields including Cornu Ammonis (CA1–3), subiculum (Sub), and dentate gyrus (DG), as well as the adjacent para-hippocampus (PHC) and entorhinal cortex (ERC), were segmented automatically using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. The relationship between tauopathy/volume of the hippocampal subfields and assessment scores was calculated using partial correlation analysis under different amyloid status, by controlling age, gender, education, apolipoprotein E (APOE) allele ɛ4 carrier status, and, time interval between the acquisition time of tau PET and amyloid PET scans.Results: Compared with amyloid negative (A−) group, individuals from amyloid positive (A+) group are more impaired based on the Mini-mental State Examination (MMSE; p = 3.82e-05), memory (p = 6.30e-04), executive function (p = 0.0016), and ADAS-cog-13 scores (p = 5.11e-04). Significant decrease of volume (CA1, DG, and Sub) and increase of tau deposition (CA1, Sub, ERC, and PHC) of the hippocampal subfields of both hemispheres were observed for the A+ group compared to the A- group. Tauopathy of ERC is significantly associated with memory score for the A- group, and the associated regions spread into Sub and PHC for the A+ group. The relationship between the impairment of behavior or executive function and tauopathy of the hippocampal subfield was discovered within the A+ group. Leftward asymmetry was observed with the association between assessment scores and tauopathy of the hippocampal subfield, which is more prominent for the NPI score for the A+ group.Conclusion: The associations of tauopathy/volume of the hippocampal subfields with clinical symptoms provide additional insight into the understanding of local changes of the human HF during the AD continuum and can be used as a reference for future studies.

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