Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study

Objective: To 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.

Methods: The 2 independent observational, cross-sectional cohorts included (1) in vivo community-dwelling, clinically normal adults from the University of California, San Francisco Memory and Aging Center who completed lumbar puncture and MRI (exclusion criteria, Clinical Dementia Rating score >0) and (2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In vivo measures included CSF synaptic proteins (synaptotagmin-1, synaptosome associated protein-25, neurogranin, and growth associated protein-43), β-amyloid (Aβ_42/40), tau phosphorylated at amino acid 181 (ptau₁₈₁), and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, vesicle associated membrane protein (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).

Results: Sixty-eight in vivo older adults (age 71 years, 43% female) and 633 decedents (age 90 years, 68% female, 34% clinically normal) were included. Each in vivo CSF synaptic protein moderated the relationship between Aβ_42/40 and ptau₁₈₁ (-0.23 < β < -0.12, p < 0.05) and the relationship between ptau₁₈₁ and GMV (-0.49 <β < -0.32, p < 0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aβ-ptau₁₈₁ and ptau₁₈₁-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 <β < -0.08, p < 0.05).

Conclusions: Pathogenic relationships of Aβ and tau may depend on synaptic state. Synaptic markers may help identify risk or resilience to AD proteinopathy.