Distinct tau pathologies in the nucleus basalis of Meynert between early-onset and late-onset Alzheimer's disease patients revealed by positron emission tomography

Background: Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). Objective: To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using ¹⁸F-florzolotau PET and examine correlations with cognitive function. Methods: Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent ¹⁸F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess ¹⁸F-florzolotau binding to tau deposits. Results: EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant ¹⁸F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. Conclusions: This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. ¹⁸F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.