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In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain and synapses are lost. Evidence from mouse models indicates that tau spreads trans -synaptically from pre- to postsynapses and that oligomeric tau is synaptotoxic, but data on synaptic tau in human brain are scarce. Here we used sub-diffraction-limit microscopy to study synaptic tau accumulation in postmortem temporal and occipital cortices of human Alzheimer's and control donors. Oligomeric tau is present in pre- and postsynaptic terminals, even in areas without abundant fibrillar tau deposition. Furthermore, there is a higher proportion of oligomeric tau compared with phosphorylated or misfolded tau found at synaptic terminals. These data suggest that accumulation of oligomeric tau in synapses is an early event in pathogenesis and that tau pathology may progress through the brain via trans -synaptic spread in human disease. Thus, specifically reducing oligomeric tau at synapses may be a promising therapeutic strategy for Alzheimer's disease. [Display omitted] • Oligomeric tau is present in synapses in Alzheimer's disease cortex • There is more oligomeric tau than phosphorylated or misfolded tau in synapses • Synaptic oligomeric tau is present even in areas without tangles • Oligomeric tau spreads from pre to post synapses in a mouse model Colom-Cadena and colleagues demonstrate using sub-diffraction-limit microscopy that synaptic oligomeric tau is a likely culprit in the spread of tau pathology through the brain in Alzheimer's disease. These data indicate that reducing oligomeric tau at synapses may be a promising therapeutic strategy to stop disease progression. [ABSTRACT FROM AUTHOR]