Improving Sleep and AD Biomarkers: A Pilot RCT of Citicoline

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Abstract Sleep disturbances are prevalent in up to 45% of persons with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Based on the growing recognition that prodromal stages of Alzheimer’s disease (MCI due to AD) are the optimal time for interventions aimed at modifying neurobiology, and sleep disturbances are commonly observed during this stage, sleep interventions are an increasingly attractive therapeutic target. Reduced percentage rapid eye movement (REM) sleep is characteristic of MCI due to AD patients, even in early stages of the disease process, which is likely due to impairment of cholinergic innervation necessary for the transition to REM sleep. The cholinergic system is involved in both AD pathology and sleep-wake regulation, and thus interventions targeting cholinergic function have the potential to improve AD-associated sleep disruption. The PI’s recently completed NIH R00 study discovered that lower plasma choline levels and increased inflammation is associated with disrupted sleep in non-AD individuals. Preliminary work from the PI and others show lower choline levels are also observed in patients with both MCI and AD. As there is a known bidirectional relationship between sleep disturbances and cognitive impairment, our team has previously proposed neuroinflammation as a potential mediator. Citicoline is an endogenous precursor of ACh and phospholipids. While Citicoline has been found to improve memory in a recent randomized clinical trial, to date, no studies have examined whether Citicoline improves REM sleep %, inflammatory, or AD biomarkers in individuals with MCI due to AD. We hypothesize that supplementation of Citicoline will result in improvement in % REM sleep, inflammation, and AD biomarkers. We will conduct a 3-month randomized, double-blind, placebo-controlled clinical trial comparing Citicoline versus placebo in 100 (50 per group) individuals with MCI due to AD. The first aim is to determine whether the Citicoline group shows improvements in % REM sleep and plasma choline compared to the placebo group from baseline to follow up. The second aim is to determine whether the Citicoline has reductions in inflammation (Interleukin-6 (IL-6) and (Tumor Necrosis Factor-α (TNF- α)), and levels of AD biomarkers (CSF Aβ42/Aβ40, total tau and p-tau 181) compared to the placebo group from baseline to follow up. We will test these hypotheses by leveraging an existing cohort from the Alzheimer’s Disease Research Cohort (ADRC) of 100 individuals with MCI due to AD. Baseline and follow-up assessments at 3 months will consist of sleep questionnaires, 2 nights of the Sleep Profiler PSG2 home sleep device, and 7 nights of wrist actigraphy. Investigators on our team have extensive experience in biomarkers, sleep, and Alzheimer’s disease. Positive outcomes from this pilot project will show that Citicoline improves sleep, inflammation, and AD biomarkers in persons with MCI due to AD, which will enable larger studies to confirm these findings and improve the health and well-being of older adults.