Suvorexant Acutely Decreases Tau Phosphorylation and Aß in the Human CNS.

OBJECTIVE: In Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid-ß levels and amyloid plaques in mouse models overexpressing amyloid-ß, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid-ß, tau, and phospho-tau. METHODS: Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid-ß, tau, and phospho-tau via immunoprecipitation and liquid chromatography-mass spectrometry. RESULTS: The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-ß ~10% to 20% compared to placebo starting 5 hours after drug administration. INTERPRETATION: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-ß concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023;94:27-40.

Adverse driving behaviors are associated with sleep apnea severity and age in cognitively normal older adults at risk for Alzheimer's disease.

Alzheimer's disease (AD) pathology accumulates for decades before the onset of cognitive decline. Cognitively normal individuals with biomarker evidence of AD brain pathology (i.e. biomarker + or preclinical AD) can be differentiated from individuals without AD brain pathology based on naturalistic driving data, such as hard acceleration or braking and speeding, measured using in-vehicle dataloggers. Older adults are at increased risk of injury and death from motor vehicle crashes and driving cessation is also linked to negative health outcomes. Identifying potentially modifiable risk factors that increase driving risk may prolong safe driving in old age. Sleep apnea is associated with adverse driving behaviors across the age span. In this study, we hypothesized that high-risk driving behaviors would be associated with increased sleep apnea severity and AD pathology. We found that higher sleep apnea severity measured by a home sleep apnea test was associated with a higher incidence of adverse driving behaviors even after controlling for multiple confounders (ß = 0.24 ±â€…0.09, p < 0.01). This association was independent of AD biomarker positivity (i.e. increased t-tau/Aß 42 ratio). Increasing age was associated with a higher likelihood of high-risk driving behaviors in individuals with AD brain pathology (ß = 0.12 ±â€…0.04, p < 0.01), but a lower likelihood in individuals without AD brain pathology (ß = -0.06 ±â€…0.03, p < 0.05). These findings suggest that adverse driving behaviors linked to a higher rate of traffic crashes in older adults are associated with sleep apnea severity and AD pathology even in cognitively unimpaired individuals. Further studies are needed to determine if treatment of sleep apnea decreases high-risk driving behaviors and therefore motor vehicle crashes.

Comparison of single-channel EEG, actigraphy, and sleep diary in cognitively normal and mildly impaired older adults.

STUDY OBJECTIVES: Multiple methods for monitoring sleep-wake activity have identified sleep disturbances as risk factors for Alzheimer disease (AD). In order to identify the level of agreement between different methods, we compared sleep parameters derived from single-channel EEG (scEEG), actigraphy, and sleep diaries in cognitively normal and mildly impaired older adults. METHODS: Two hundred ninety-three participants were monitored at home for up to six nights with scEEG, actigraphy, and sleep diaries. Total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), and wake after sleep onset (WASO) were calculated using each of these methods. In 109 of the 293 participants, the ratio of cerebrospinal fluid concentrations of phosphorylated tau (p-tau) and amyloid-ß-42 (Aß42) was used as a biomarker for AD pathology. RESULTS: Agreement was highest for TST across instruments, especially in cognitively normal older adults. Overall, scEEG and actigraphy appeared to have greater agreement for multiple sleep parameters than for scEEG and diary or actigraphy and diary. Levels of agreement between scEEG and actigraphy overall decreased in mildly impaired participants and those with biomarker evidence of AD pathology, especially for measurements of TST. CONCLUSIONS: Caution should be exercised when comparing scEEG and actigraphy in individuals with mild cognitive impairment or with AD pathology. Sleep diaries may capture different aspects of sleep compared to scEEG and actigraphy. Additional studies comparing different methods of measuring sleep-wake activity in older adults are necessary to allow for comparison between studies using different methods.