Insomnia symptoms and markers of preclinical Alzheimer’s disease in the community

Abstract Background Amyloid production increases during wakefulness before being cleared during sleep. Insomnia is one of the commonest sleep disorders, yet its relationship to core markers of preclinical Alzheimer’s disease remains unknown. We investigated the cross‐sectional relationship between insomnia symptom severity, APOE e4 carriage, and cerebrospinal spinal fluid (CSF) concentrations of Alzheimer’s disease biomarkers in a non‐demented community‐sample aged 43‐67 years. Method 66 participants from the Healthy Brain Project Biomarker Sub‐study (age = 58±6 years; MMSE = 29±7; 68% women) completed a lumbar puncture, two weeks of actigraphy to measure sleep and wake patterns, and the Insomnia Severity Index (ISI) to measure insomnia symptom severity over the past two weeks. The ISI was split into two groups (normal vs. high [>7]) based on established cut‐off values (42% of the sample were high). Two core insomnia features were captured: Difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (high wake after sleep onset (WASO) duration and number of awakenings), with each variable classified as the top 25 th percentile versus the remainder of the sample. Analysis of covariance was used to compare CSF amyloid‐beta 42 (Aβ42), phosphorylated tau 181 (p‐tau181), total‐tau, and neurofilament light chain protein (NfL) across each of the sleep groups, adjusting for age and sex. Result Persons with high insomnia symptom severity had higher CSF Aβ42 levels (p=0.033, d=0.58). Difficulty maintaining sleep (both high WASO and number of awakenings) was also associated with higher Aβ42 levels (p=0.023, d=0.77 for WASO; p=0.013, d=0.92 for awakenings), whereas difficulty initiating sleep was not (p= 0.776, d=0.08). The sleep variables were not associated with p‐tau181, total‐tau, or NfL levels (p>0.05). APOE e4 modified the association between WASO and Aβ42. The strength of the relationship between higher WASO (versus normal) and Aβ42 was stronger in e4 carriers, compared to non‐carriers (F(df) = 6.94 (1, 44), p=0.012). Conclusion In this relatively young sample, symptoms and features of insomnia were associated with higher CSF Aβ42 levels. These findings may reflect increased amyloid production due to acute sleep disruption. Longitudinal studies are needed to determine whether sustained sleep disruption associates with amyloid accumulation over time.