Sleep and APOE-4 have a synergistic effect on plasma biomarkers and longitudinal cognitive decline in older adults

Background: Sleep disorders are prevalent among patients with Alzheimer's disease (AD), and the APOE epsilon 4 genotype is a key genetic risk factor for sporadic AD. However, the combined effect of the genotype and sleep disorders on cognitive decline remains uncertain. Methods: A total of 972 participants were drawn from the SILCODE cohort, comprising 655 without the epsilon 4 allele (APOE-) and 317 with epsilon 4 allele (APOE+). Data were collected, including neuropsychological assessments, sleep measurements, plasma biomarkers, and PET imaging. A Sleep Composite Index (SCI) was created, categorizing participants into high risk (Sleep+) and low risk (Sleep-). Results: Significant predictions of dementia risk associated with plasma p-tau181, neurofilament light chain (NfL), and SCI. Individuals with both Sleep+ and APOE+ had a higher risk of dementia compared to those with Sleep-. The Sleep+/APOE+ group had higher plasma NfL levels than the Sleep-/APOE- group. Similar trends emerged in plasma NfL levels among the A beta PET-positive subgroup. Plasma NfL levels explained 23% of the relationship between SCI and cognitive impairment. Conclusion: Our study highlights sleep disorder was associated with cognitive decline, with plasma NfL playing a partial mediating role. These findings explain how sleep disorders affect cognitive function and emphasize the importance of healthy sleep for older adults.