Objective:

To pinpoint genetic variations influencing Long COVID Cognitive
Impairment (LCCI).

Background:

LCCI is a frequent and poorly understood consequence of
COVID-19, imposing a growing burden on society.

Design/Methods:

We employed next-generation sequencing to analyze a
pre-selected 400-variant panel associated with neuroinflammation and related
pathways. We analyzed 49 LCCI cases and 57 post-COVID controls without
cognitive impairment. Fisher's exact test, Benjamini-Hochberg and Bonferroni
methods (p<0.05), and in-silico functional evaluation were performed.

Results:

LCCI patients exhibited significantly higher frequency of rs40030
(G/A>G) variant in the S-Phase Kinase-Associated Protein 2 (SKP2) gene
(p=0.006), while controls exhibited significantly higher frequency of the
alternative genotype (A/A>G) for the same variant (p=0.036). The region where
the variant is located corresponds to regions associated with the cognitive areas
of the brain. One proposed mechanism of LCCI is SARS-CoV-2 inhibits
autophagy, leading to dysregulated cellular metabolism and excessive
inflammatory and autoimmune responses. Interestingly, SKP2 is an inhibitor of
autophagy. In-silico analysis showed the G/A variant amplifies the expression of
SKP2 in the brain, while the A/A variant does the opposite. Thus, SKP2 may
play a vital role in LCCI. rs3212227 (T/G>T) of IL-12B presented higher
frequency in LCCI cases (p=0.011). IL-12B is widely related to
neurodegenerative disorders such as Alzheimer's disease (AD). This genotype
is known to amplify IL-12B expression and was significantly related to AD risk.
Finally, LCCI patients exhibited a significantly higher frequency of rs35362851
(T/G>T) in the Retinoid X Receptor Alpha (RXRA) gene. This genomic region
corresponds to an enhancer in frontal cortex, cingulate gyrus and hippocampus.
Several variants in RXRA are associated with general cognitive ability and AD
risk.

Conclusions:

This investigation revealed distinct genetic variants influencing
LCCI and warrants further investigation to elucidate their precise roles in this
disease. This knowledge could guide the development of personalized
prognostic tools and potentially therapeutic strategies.