Associations of hippocampal volumes, brain hypometabolism, and plasma NfL with amyloid, tau, and cognitive decline

INTRODUCTION: Various indicators of neurodegeneration (N) are used in the assessment of neuronal injury in Alzheimer's disease (AD). The heterogeneity of such indicators is less clear. METHODS: A total of 416 individuals with different cognitive statuses were recruited for this study. Differential associations of hippocampal volume (HV), 18F-fluorodeoxyglucose positron emission tomography (FDG PET) standardized uptake value ratios (SUVRs), and plasma neurofilament light chain (NfL) levels with amyloid beta (Aβ)–tau pathology and cognitive impairment were examined. RESULTS: HV decreased early during the high Aβ burden but tau-negative stage. FDG PET SUVRs and plasma NfL levels notably changed at tau-positive stages. HV and plasma NfL correlated with cognitive scores in the early to middle stages, while FDG PET SUVRs aligned with cognitive decline from the middle to late stages. Hippocampal atrophy and inferior parietal hypometabolism increased the risk of cognitive impairment in A+T+, while adding NfL+ had no additional impact within the distinct A/T groups. DISCUSSION: Different indicators of N have varying relationships to AD pathology and cognitive impairment. Highlights: Hippocampal atrophy emerges early with a high amyloid beta burden and exacerbates during the tau-positive phase. Brain hypometabolism and elevated plasma neurofilament light chain (NfL) levels appear mainly in tau-positive stages. Hippocampal volume and plasma NfL levels correlate with cognitive decline in the early to middle stages, while 18F-fluorodeoxyglucose positron emission tomography standardized uptake value ratios in the middle to late stages. Hippocampal atrophy and inferior parietal hypometabolism raise the risk of cognitive impairment in amyloid/tau–positive individuals while adding NfL+ shows no additional effect.