Sleep as an Active Modifier of Blood-Based Biomarkers in Alzheimer’s Disease

Blood-based biomarkers (BBMs) for Alzheimer' s disease (AD), including phosphorylated tau at threonine 217, 181 (pTau217, pTau181), the amyloid- 42 to amyloid- 40 ratio (A42/40), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), are emerging as a cost-effective platform for early screening and detection.Increase in relevant research is grounded in the assumption that plasma biomarkers primarily reflect stable, pathologydriven brain processes.However, emerging evidence suggests that diverse demographic factors and clinical comorbidities can influence BBM levels [1].One of them is sleep, not merely a behavioral state but a powerful biological modulator of protein clearance, neuroinflammation, and brain-blood transport [2,3].For this reason, I propose that sleep should be conceptualized as an active modifier of BBMs, as interpretations that do not account for sleep may lead to misclassification, particularly in preclinical disease where biomarker changes are subtle.Although BBMs are often viewed as highly stable indicators, accumulating findings suggest they are sensitive to sleep-related processes.A recent study demonstrated that disrupted rest-activity rhythm in midlife women has been linked to poorer processing speed and higher plasma phosphorylated tau at threonine 231 (p-Tau231) levels.Moreover, poorer sleep quality was associated with higher plasma p-Tau231 levels and interacted with AD genetic risk to influence p-Tau231 concentrations [4].Sleep disorders such as obstructive sleep apnea (OSA) also affected the BBM levels, with blood total A, A42, A40, and total tau all elevated in OSA patients [5].Furthermore, p-Tau217 was reported to have a diurnal variation, with the lowest level observed in the morning and the highest values observed in the afternoon/early evening [6].Interestingly, these dynamic changes in BBMs were influenced by other known risk factors for AD, such as sex and apolipoprotein E genotype [7].In A+ cognitively unimpaired individuals, sleep plays a critical role in AD at the stage when biomarkers are most informative for early detection.In this preclinical phase-where overt cognitive symptoms are absent-biomarkers play an integral role in early detection and risk stratification, yet their absolute levels and longitudinal changes are usually subtle and vulnerable to fluctuation.Accumulating evidence indicates that older adults at genetic or biomarker-defined risk of AD frequently exhibit early sleep disturbances, including reduced slow-wave activity, impaired sleep spindle density, circadian misalignment, and increased nocturnal fragmentation-alterations that have been linked to A deposition and tau propagation [8,9].A central paradox emerges at this stage: individuals in the earliest phases of AD pathology, in whom biomarkers are most clinically valuable, may also experience the greatest sleeprelated variability in biomarker levels.Experimental and human studies demonstrate that sleep-wake dynamics directly influence A and tau concentrations through activity-dependent release and clearance mechanisms [10].As a result, a BBM drawn after a night of poor sleep may be interpreted as abnormal or "borderline positive, " whereas the same individual could fall below diagnostic thresholds following consolidated sleep.This variability has important implications not only for clinical diagnosis but also for longitudinal tracking, risk stratification, and treatment-response monitoring in prevention-orientated settings.