Abstract
Early neuropathological changes characteristic of late-onset Alzheimer’s disease (LOAD) involve brain stem and limbic structures that regulate neurovegetative functions, including sleep–wake rhythm. Indeed, sleep pattern is an emerging biomarker and a potential pathophysiological mechanism in LOAD. We hypothesized that cognitively asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) would display a series of circadian rhythm abnormalities prior to the onset of objective cognitive alterations. We tested 31 children of patients with LOAD (O-LOAD) and 19 healthy individuals without family history of Alzheimer’s disease (control subjects, CS) with basic tests of cognitive function, as well as actigraphy measures of sleep–wake rhythm, cardiac autonomic function, and bodily temperature. Unexpectedly, O-LOAD displayed subtle but significant deficits in verbal episodic memory (Rey Auditory Verbal Learning Test delayed recall 10.6 ± 0.4 vs. 8.6 ± 0.6, t = 4.97, df = 49, p < 0.01) and language (Weschler’s vocabulary 51.4 ± 1.3 vs. 44.3 ± 1.5, t = 2.49, df = 49, p < 0.001) compared to CS, even though all participants had results within the clinically normal range. O-LOAD showed a phase-delayed rhythm of body temperature (2.56 ± 0.47 h vs. 3.8 ± 0.26 h, t = 2.48, df = 40, p = 0.031). Cognitive performance in O-LOAD was associated with a series of cardiac autonomic sleep–wake variables; specifically indicators of greater sympathetic activity at night were related to poorer cognition. The present results suggest sleep pattern deserves further study as a potential neurobiological signature in LOAD, even in middle-aged, at risk individuals.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes up to 80% of all dementia cases worldwide (Alzheimer’s Association, 2016)
O-late-onset Alzheimer’s disease (LOAD) showed a delayed phase in the circadian rhythm of body temperature compared to control subjects (CS) (Table 1)
Measures of sleep– wake cycle in the actigraphy, cardiac autonomic variables, and relative gray matter (GM) and white matter (WM) brain volumes were similar in both groups as well (Table 1)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes up to 80% of all dementia cases worldwide (Alzheimer’s Association, 2016). Significant in vivo Aβ deposition is present in a substantial number of cognitively normal elderly individuals, and it is associated with gray matter (GM) changes not characteristic of the early phases of neurodegeneration of AD (Sepulcre et al, 2016). In spite of this evident lack of correlation between Aβ deposition and cognitive symptoms, a number of pharmacological agents targeting Aβ accumulation have failed or even resulted in worse outcomes than placebo. This group of experimental drugs (including anti-Aβ antibodies seeking to improve clearance of brain amyloid, and drugs interfering with the synthesis of new amyloid) have met with one of the highest failure rates in any therapeutic area in the history of medicine (Cummings et al, 2014)
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