APOE is a presynaptic protein that accumulates with age and modulates neurotransmitter release.

The synaptic vesicle (SV) cycle is the fastest membrane trafficking and protein sorting process in biology. It underlies neuronal communication and cognition, yet synaptic function declines during normal aging, increasing vulnerability to neurologic disease. How the SV cycle is maintained across the lifespan of a complex organism remains unclear. Here, we used wild-type mice (C57BL/6J) to define the age- and sex-stratified molecular landscape of SVs and identified apolipoprotein E (APOE) as an abundant presynaptic protein further enriched in aged female samples. Super-resolution imaging, cell-type selective expression, and protease protection assays demonstrate that APOE originates from astroglia and associates with the cytosolic face of SVs. Using iGluSnFR and pHluorin optophysiology, we find that both decreased and increased APOE levels impair neurotransmission during stimulus trains. Together, these findings place APOE at the synapse and establish it as a cell-nonautonomous regulator of the SV cycle.