CRHR1 Gene Copy Number Variations, Chronic Viral Infections, and Age as Correlates of Cognitive Impairment in Adults After SARS-CoV-2 Infection

Cognitive impairment is a frequent but heterogeneous consequence of SARS-CoV-2 infection, with objective cognitive deficits not always aligning with subjective cognitive complaints. Age, nutritional status, and stress-related biological pathways may contribute to this variability. The corticotropin-releasing hormone receptor 1 (CRHR1), a key regulator of stress and neuroendocrine responses, represents a biologically plausible candidate for post-infection cognitive vulnerability. In this pilot case–control study, we investigated associations between CRHR1 copy number variations (CNVs), prior viral exposures, and cognitive outcomes in adults following SARS-CoV-2 infection. Objective cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) and RBANS, alongside evaluation of subjective cognitive complaints and depressive symptoms. Analyses accounted for age and circulating levels of vitamins B12, B9, and vitamin D. CRHR1 CNVs affecting specific exons (Exon 1 [210 nucleotides] and Exon 11) were associated with objective cognitive impairment, whereas subjective cognitive complaints were more closely related to depressive symptoms than measurable cognitive deficits. Associations with age and certain viral seropositivities (HSV-1, HSV-2, and Hepatitis A) were also observed with objective cognitive outcomes; however, these findings should be interpreted cautiously given their exploratory nature. This study highlights CRHR1 CNVs as potential modifiers of objectively measured post-COVID-19 cognitive impairment and underscores the importance of distinguishing subjective cognitive complaints from objective cognitive dysfunction, providing a framework for future mechanistic and longitudinal studies.