Long COVID “Brain Fog” May Be Linked to an Underlying Molecular Mechanism

Cognitive impairment associated with the reported chronic condition often referred to as “long COVID” may be linked to an underlying molecular mechanism characterized by increased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor density across the brain according to new findings published in Brain Communications. In the study, PET imaging data from the brains of individuals with long COVID showed significantly higher densities of AMPA receptors compared with healthy controls. The findings suggest that AMPA receptors—proteins involved in synaptic transmission and memory—may contribute to long COVID–associated “brain fog.” Additionally, the study authors note that the findings may identify the AMPA receptor as a potential therapeutic target for future strategies to treat people with long COVID.

In the case-control study, researchers compared [¹¹C]K-2 PET data from 30 individuals with long Covid cognitive impairment—defined as subjective cognitive impairment as sequelae of COVID-19 (SARS-CoV-2) infection—with data from 80 healthy control participants. The analysis measured standardized uptake value ratios (SUVR) to estimate AMPA receptor density across brain regions and assessed correlations with plasma cytokines and neuropsychological testing. Machine learning models were applied to determine whether imaging data was able to distinguish long COVID cognitive impairment cases from healthy controls.

Key findings from the study include the following:

• Individuals with long COVID cognitive impairment showed widespread elevations in AMPA receptor density compared with healthy controls (P<.05, T>1.66, 1-tailed, false discovery rate corrected [FDRc]).
• AMPA receptor density was found to be positively correlated with plasma TNFSF12 (tumor necrosis factor super family member 12) levels and negatively correlated with plasma CCL2 (C-C motif chemokine ligand 2) levels.

• AMPA receptor density data was found to have high diagnostic accuracy for long COVID—associated cognitive impairment with 100% sensitivity and 91.2% specificity.

The study authors theorize that increased AMPA receptor activity throughout the brain may cause abnormal information processing associated with long COVID–related cognitive impairment, with heightened excitatory signaling that may cause neuronal damage.

Source: Fujimoto Y, Abe H, Eiro T, et al. Systemic increase of AMPA receptors associated with cognitive impairment of long COVID. Brain Commun. 2025;7(5):fcaf337. Published 2025 Oct 1. doi:10.1093/braincomms/fcaf337