Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study. (20th July 2021)

• Record Type: Journal Article
• Authors: Casaletto, Kaitlin B.; Zetterberg, Henrik; Blennow, Kaj; Brinkmalm, Ann; Honer, William; Schneider, Julie A.; Bennett, David A.; Djukic, Nina; You, Michelle; Weiner-Light, Sophia; Fonseca, Corrina; Miller, Bruce L.; Kramer, Joel
• Is Part Of: Neurology. Volume 97:Number 3(2021)
• Publication Date: 2021-07-20
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000012145
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : 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 (Aβ42/40 ), 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 Aβ42/40 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.