The study investigates the association between elevated cerebrospinal fluid (CSF) levels of GAP-43, a presynaptic protein, and accelerated tau accumulation and spread in Alzheimer's disease (AD). Using data from 93 AD patients across the spectrum of cognitive impairment, the researchers found that higher CSF GAP-43 levels were associated with faster Aβ-related tau accumulation, particularly in brain regions closely connected to subject-specific tau epicenters. This suggests that synaptic changes, as measured by increased CSF GAP-43, may drive the trans-synaptic spread of tau pathology. The findings indicate that synaptic changes could be key targets for preventing tau spreading in AD, contributing to the understanding of how Aβ and synaptic changes jointly drive tau aggregation and spread, ultimately leading to neurodegeneration and cognitive decline.The study investigates the association between elevated cerebrospinal fluid (CSF) levels of GAP-43, a presynaptic protein, and accelerated tau accumulation and spread in Alzheimer's disease (AD). Using data from 93 AD patients across the spectrum of cognitive impairment, the researchers found that higher CSF GAP-43 levels were associated with faster Aβ-related tau accumulation, particularly in brain regions closely connected to subject-specific tau epicenters. This suggests that synaptic changes, as measured by increased CSF GAP-43, may drive the trans-synaptic spread of tau pathology. The findings indicate that synaptic changes could be key targets for preventing tau spreading in AD, contributing to the understanding of how Aβ and synaptic changes jointly drive tau aggregation and spread, ultimately leading to neurodegeneration and cognitive decline.