Circadian biomarkers in asymptomatic offspring of patients with late-onset Alzheimer's disease and their relationship with cognitive performance

Abstract

Introduction: Early neuropathological changes characteristic of late-onset Alzheimer´s disease (LOAD) impact structures that regulate circadian rhythms and particularly sleep. Indeed, sleep pattern is emerging as a potential biomarker, mechanistic pathway and treatment target in LOAD. We hypothesized that circadian rhythm anomalies would already be present in asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) prior to cognitive decline.Materials and methods: We tested 35 subjects with at least one parent with LOAD (O-LOAD) and 31 healthy individuals without family history of Alzheimer´s disease (control subjects, CS) with a series of cognitive tests, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function via heart rate variability (HRV), and bodily temperature.Results: O-LOAD displayed subtle yet significant deficits in verbal episodic memory (RAVLT learning 48.32 ± 1.59 vs. 44.12 ± 1.21, p = 0.005; delayed recall 10.55 ± 0.38 vs. 8.68 ± 0.52, p = 0.005) and language (Vocabulary 50.5 ± 1.06 vs. 45.06 ± 1.48, p= 0.004) compared to CS. O-LOAD showed a more extended sleep duration (439.26 min ± 9.41 vs. 473.66 min ± 10.57, p = .018) and reduced sleep efficiency (97.07 % ± .41 vs. 95.75 % ± .48, p = .042). No significant differences were found for body temperature or HRV variables. Correlations between increased sleep duration and poorer cognition were found in CS but not in O-LOAD. Improved cognitive performance was associated to indicators of greater sympathetic activity.Conclusions: Our results support the hypothesis that sleep pattern disturbances are already present very early on in relatively young asymptomatic subjects. The unexpected reduced cognitive results found in O-LOAD suggest that cognitive decline could start earlier than anticipated in the form of subtle cognitive changes within the clinically normal range. It is widely accepted that sleep pattern disturbances would result in cognitive alterations. Taken these information together with the correlations between sleep duration and cognition present in CS but absent in O-LOAD suggest some impairment in the mechanisms underlying the sleep-cognitive relationship. Sleep pattern deserves further study as a potential biomarker in LOAD, even in healthy middle-aged individuals.