Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS

Abstract

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-β levels and amyloid plaques in mouse models overexpressing amyloid-β, 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-β, 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-β, 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-β ~10% to 20% compared to placebo starting 5 hours after drug administration.

Interpretation: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-β 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.

Figure 1:

Participant flow diagram and study design. A. Eighty-eight participants were screened for the study and 46 participants screened failed. Forty-two participants were randomized. Four participants were withdrawn from the study after randomization but before CSF was collected or study interventions administered. The lumber catheter could not be placed for two participants. One participant withdrew due to the COVID-19 pandemic and one participant was excluded after an exclusion diagnosis was found after additional medical records were received. Thirty-eight participants completed the study in the placebo (N=13), suvorexant 10 mg (N=13), and suvorexant 20 mg (N=12) groups. B. Study design during admission to the Clinical Translational Research Unit for lumbar catheter placement and CSF sampling.

Figure 2:

Sleep parameters for each group on nights 1 and 2 after receiving either placebo, suvorexant 10 mg, or suvorexant 20 mg. On both night 1 and night 2, total sleep time (A, B), sleep efficiency (C, D), time spent in non-rapid eye movement (NREM) stage 2 sleep (E, F), time spent in NREM stage 3 sleep (G, H), and time spent in rapid eye movement sleep (I, J) were not significantly increased between placebo and treatment groups. There was a trend for higher sleep efficiency in suvorexant 20 mg group on night 1 (p=0.07). Red: placebo; Blue: suvorexant 10 mg; Green: suvorexant 20 mg. Mean and standard error bars are shown. P-values corrected using Dunnett’s multiple comparison’s test.

Figure 3:

Effect of suvorexant on unphosphorylated tau (i.e., total tau). Tau-threonine-181 (T181) was normalized to change from hour 0 for ng/ml (A), percent change from hour 0 (B), and percent change from hour 6 (C). The percent change from hour 0 was significantly decreased at hour 2 in the suvorexant 20 mg group compared to placebo, but otherwise there were no significant group differences. Tau-serine-202 (S202) was normalized to change from hour 0 for ng/ml (D), percent change from hour 0 (E), and percent change from hour 6 (F). The percent change from hour 0 was significantly decreased at hour 2 in the suvorexant 20 mg group compared to placebo, but otherwise there were no significant group differences. Tau-threonine-217 (T217) was normalized to change from hour 0 for ng/ml (G), percent change from hour 0 (H), and percent change from hour 6 (I). The percent change from hour 6 was significantly decreased at hour 8 in the suvorexant 10 mg group compared to placebo, but otherwise there were no significant group differences. Red: placebo; Blue: suvorexant 10 mg; Green: suvorexant 20 mg. Error bars indicate standard error. The vertical dashed lines are at hours 1 and 25 when placebo or suvorexant was administered. The vertical solid line is at hour 6. The horizontal dashed line is at the normalized baseline. The shaded regions are the overnight periods. *p < 0.05 after correction for multiple comparisons.

Figure 4:

Effect of suvorexant on phosphorylated tau. Phosphorylated-tau-threonine-181 (pT181) was normalized to change from hour 0 for ng/ml (A), percent change from hour 0 (B), and percent change from hour 6 (C). The percent change from hour 0 was significantly decreased at hour 2 in the suvorexant 20 mg group compared to placebo, but otherwise there were no significant group differences. Phosphorylated-tau-serine-202 (pS202) was normalized to change from hour 0 for ng/ml (D), percent change from hour 0 (E), and percent change from hour 6 (F). The percent change from hour 6 was significantly decreased at hours 4 and 18 in the suvorexant 20 mg group compared to placebo, but otherwise there were no significant group differences. Phosphorylated-tau-threonine-217 (pT217) was normalized to change from hour 0 for ng/ml (G), percent change from hour 0 (H), and percent change from hour 6 (I). The percent change from hour 0 was significantly decreased at hour 2 in the suvorexant 20 mg group compared to placebo, but otherwise there were no significant group differences. Red: placebo; Blue: suvorexant 10 mg; Green: suvorexant 20 mg. Error bars indicate standard error. The vertical dashed lines are at hours 1 and 25 when placebo or suvorexant was administered. The vertical solid line is at hour 6. The horizontal dashed line is at the normalized baseline. The shaded regions are the overnight periods. *p < 0.05 after correction for multiple comparisons.

Figure 5:

Effect of suvorexant on phosphorylated tau/unphosphorylated tau ratio. Phosphorylated-tau-threonine-181/unphosphorylated-tau-threonine-181 ratio (pT181/T181) was decreased at multiple time points in both the non-normalized (A) and normalized to change from hour 0 (B). Suvorexant 20 mg decreased pT181/T181 at hours 14, 16, 26–36 compared to placebo. Suvorexant 10 mg decreased pT181 at hour 26 compared to placebo. For the data normalized to percent change from hour 0, the area under the curve (AUC) across the entire sampling period (hours 0–36) for pT181/T181 was significantly reduced in the suvorexant 20 mg group compared to placebo (C). There were no significant group differences for both the phosphorylated-tau-serine-202/unphosphorylated-tau-threonine-202 ratio (pS202/S202) (D-F) or the phosphorylated-tau-threonine-217/unphosphorylated-tau-threonine-217 ratio (pT217/T217) (G-I). pS202/S202 was decreased from placebo but not significantly. Red: placebo; Blue: suvorexant 10 mg; Green: suvorexant 20 mg. Error bars indicate standard error. The vertical dashed lines are at hours 1 and 25 when placebo or suvorexant was administered. The horizontal dashed line is at the normalized baseline. The shaded regions are the overnight periods. *p < 0.05, **p < 0.01, ***p < 0.001 after correction for multiple comparisons.

Figure 6:

Effect of suvorexant on amyloid-β (Aβ). Aβ38, Aβ40, and Aβ42 were normalized to change from hour 0 for ng/ml (A, D, G), percent change from hour 0 (B, E, H), and percent change from hour 6 (C, F, I). When normalized to hour 0 for ng/ml, Aβ38 at hour 36 was significantly decreased in the suvorexant 20 mg group compared to placebo (A). When normalized to percent change from hour 0, Aβ42 was significantly decreased in the suvorexant 20 mg group compared to placebo (H). The percent change from hour 6, five hours after the intervention was administered, showed that Aβ38, Aβ40, and Aβ42 were significantly decreased at multiple time points. Red: placebo; Blue: suvorexant 10 mg; Green: suvorexant 20 mg. Error bars indicate standard error. The vertical dashed lines are at hours 1 and 25 when placebo or suvorexant was administered. The vertical solid line is at hour 6. The horizontal dashed line is at the normalized baseline. The shaded regions are the overnight periods. *p < 0.05 and **p < 0.01 after correction for multiple comparisons.

Figure 7:

Effect of suvorexant on amyloid-β (Aβ) area under the curve (AUC). The AUC was calculated for Aβ38, Aβ40, and Aβ42 normalized to percent change from hour 0 (A-C). There were no significant differences between placebo and the intervention groups for Aβ38, Aβ40, and Aβ42. The AUC was also calculated for Aβ38, Aβ40, and Aβ42 normalized to percent change from hour 6 or five hours after the intervention was administered (D-F). There were no significant differences between placebo and the intervention groups for Aβ38 and Aβ40. However, the suvorexant 20 mg group was significantly decreased compared to placebo. Red: placebo; Blue: suvorexant 10 mg; Green: suvorexant 20 mg. Error bars indicate standard error. P-values are shown and are corrected for multiple comparisons.

Figure 8:

Dose-Response Curves. After normalization to percent change from hour 0, the group means at each time point were calculated for Aβ38, Aβ40, Aβ42, and pT181/T181. The group differences for Aβ38, Aβ40, Aβ42, and pT181/T181 at each time point were then calculated for suvorexant 10 mg vs. placebo and suvorexant 20 mg vs. placebo (A-D). Suvorexant 20 mg decreased Aβ38, Aβ40, Aβ42, and pT181/T181 across hours 0–36 compared to placebo with Aβ decreasing 20–40% from placebo and pT181/T181 decreasing 5–10% from placebo. Suvorexant 10 mg showed minimal change from placebo. Blue: suvorexant 10 mg minus placebo; Green: suvorexant 20 mg minus placebo. The vertical dashed lines are at hours 1 and 25 when placebo or suvorexant was administered. The vertical solid line is at hour 6. The horizontal dashed line is at the normalized baseline. The shaded regions are the overnight periods.