Untangling the association of amyloid-beta and tau with synaptic and axonal loss in Alzheimer's disease

It is currently unclear how amyloid-beta and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-beta and tau pathology based on F-18-flutemetamol PET and F-18-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-beta-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-beta pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-beta and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-beta and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.

Automated summary

The study found that in early Alzheimer's disease, presynaptic and postsynaptic markers are elevated and associated with more severe amyloid-beta pathology, memory decline, and changes in the default mode network. In later disease stages, abnormal levels of neurofilament light chain were observed, correlated with more tau pathology and worse global cognition.