Abstract Low titers of blood circulating natural anti-NMDAR1 autoantibodies were reported in ~10% of the general human population. Their potential effects on NMDAR functions in the brain, however, remain unknown. We developed a new method to more accurately quantify these low titers of natural anti-NMDAR1 autoantibodies. After quantifying natural anti-NMDAR1 autoantibodies in the plasma of 324 subjects (163 healthy controls; 161 Alzheimer’s disease (AD) patients), I found that AD patients carrying higher levels of natural anti-NMDAR1 autoantibodies have significantly ( p value: 0.0015) higher scores of Mini-Mental State Examination (MMSE score: 23.5) than AD patients carrying lower levels of natural anti-NMDAR1 autoantibodies (MMSE score: 21.4). No significant differences in MMSE scores were, however, found between healthy controls with either higher or lower levels of natural anti-NMDAR1 autoantibodies, indicating little harmful effect of the autoantibodies. Consistently, superior cognitive performances were found in AD patients carrying higher levels of natural anti-NMDAR1 autoantibodies in comparison with AD patients carrying lower levels of the autoantibodies. Although this association is intriguing, a causal relationship between natural anti-NMDAR1 autoantibodies and neuroprotection has not yet been established. Since anti-NMDAR1 autoantibodies can bind NMDA receptors to suppress glutamate excitotoxicity in the brain, natural anti-NMDAR1 autoantibodies may have neuroprotective effects against cognitive decline in AD patients.
Xianjin Zhou (2026) studied this question.