Background: Circadian disruption has been suggested to induce cognitive impairment and dementia. It remains unknown which brain structures are involved in the pathology. Objective: To investigate which specific brain structure alterations are associated with dementia and cognitive impairment induced by circadian disruption. Methods: Circadian disruption was represented by two accelerometer-derived circadian variables, composite phase deviations (CPD) and relative amplitude (RA), separately reflecting circadian disruption in timing and amplitude. The outcomes include brain structures (139 imaging-derived phenotypes), cognitive test performances (seven cognitive tests) and dementia (all-cause dementia, Alzheimer’s disease, vascular dementia (AD/VD) and non-AD/VD dementia). Association analysis was used to explore the relationships between circadian disruption and brain structure alterations, cognitive test performances and dementia. Mediation analysis was conducted to investigate which brain structure alterations mediated the cognitive impairment and dementia caused by circadian disruption. Findings: A total of 88 461 participants (57% female, 62.0±7.8-year old) were included. CPD and RA correlated with substantially different brain structures. All CPD-related brain structures were located in the cerebrum, whereas most RA-related brain structures were located in the cerebellum. Furthermore, only the CPD-related brain structures, including the hippocampus and thalamus, exhibited significant mediation effects accounting for up to 8.6% of the risk for dementia and 13.5% of the risk for cognitive impairment. Conclusions: Circadian disruption is associated with brain structural alterations involving dementia and cognitive impairments. Clinical implications: These results provide a novel insight into the mechanism underlying circadian disruption-induced neurological disorder and may propose potential preventive strategy.

Circadian disruption has been linked to impaired male fecundity, but its association with semen molecular phenotypes and circadian genes remains unclear. We analyzed 441 men from the Male Reproductive Health in Chongqing College Students cohort to assess whether social jetlag, an indicator of circadian disruption, was associated with whole-semen mitochondrial DNA copy number (mtDNAcn), an emerging biomarker of male fecundity. Core circadian genes related to mtDNAcn were screened using genetic polymorphism data. A light-cycle phase-shifting mouse model, Cry1-knockout mice, and testicular Cry1 re-expression models were used for experimental validation, with histology, transcriptomics, single-cell data, and proteomics analyses used to explore mechanisms. Social jetlag was associated with higher mtDNAcn in men (1.29-fold, p = 0.026), with a concordant increase in circadian-disrupted mice (1.33-fold, p = 0.010). Among core circadian genes, CRY1 showed the strongest association with mtDNAcn (p = 0.048). Cry1 knockout elevated mtDNAcn (2.18-fold, p < 0.001), whereas testicular Cry1 re-expression reduced it toward wild-type levels. Circadian disruption and Cry1 deficiency were accompanied by seminiferous epithelial disorganization, spermatogenesis-related transcriptomic changes, and altered mitochondrial pathway signatures. To our knowledge, this study is the first to identify whole-semen mtDNAcn as a circadian-disruption-associated molecular phenotype and supports CRY1 as a candidate regulator.