ObjectiveTo test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in-vivo and postmortem.MethodsTwo independent observational, cross-sectional cohorts: 1) in-vivo community-dwelling, clinically normal adults from the UCSF Memory and Aging Center completed lumbar puncture and MRI (exclusion criteria, CDR>0), and 2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In-vivo measures included cerebrospinal fluid (CSF) synaptic proteins (synaptotagmin-1, SNAP-25, neurogranin, and GAP-43), Aβ42/40, ptau181, and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, VAMP, and SNARE complex), and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins*amyloid on tau, and synaptic proteins*tau on GMV).Results68 in-vivo older adults (age=71y, 43%F) and 633 decedents (age=90y, 68%F, 34% clinically normal) were included. Each in-vivo CSF synaptic protein moderated the relationship between Aβ42/40 and ptau181 (-0.23<?s<-0.12, ps<0.05) and the relationship between ptau and GMV (-0.49<?s<-0.32, ps<0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aβ-ptau and ptau-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10<?s<-0.08, ps<0.05).ConclusionsPathogenic relationships of Aβ and tau may depend on synaptic state. Synaptic markers may help identify risk and/or resilience to AD proteinopathy
