Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults

Abstract

Background Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression. MethodsWe did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression. FindingsParticipants had a median age of 81•8 (IQR 76•3-85•7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1•39, 95% CI 1•19-1•62) and higher intradaily variability (1 SD increase, 1•22, 1•04-1•43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1•46, 95% CI 1•24-1•72), higher intradaily variability (1 SD increase, 1•36, 1•15-1•60), and lower interdaily stability (1 SD decrease, 1•21, 1•02-1•44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2•08, 95% CI 1•53-2•93), increased intradaily variability (1 SD increase, 1•97, 1•43-2•79), and decreased interdaily stability (1 SD decrease, 1•35, 1•01-1•84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability. Interpretation Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms.

Demographic characteristics associated with circadian rest-activity rhythm patterns: a cross-sectional study

“…On the other hand, we also unexpectedly found that older adults had more stable and less fragmented RAR than younger adults. This result is seemingly at variance with evidence of decreases in stability and increases in fragmentation relating to age-related neurodegenerative disorders, such as Parkinson’s disease [ 43 ] and Alzheimer’s disease [ 11 , 13 ]. However, the association between circadian rhythms and neurodegenerative disease has been reported to be bidirectional, with neurodegenerative disease also affecting circadian rhythms [ 1 , 3 ].…”

“…Another longitudinal analysis of 2930 older men also reported that, compared with participants in the highest quartile of amplitude, mesor (mean activity level) and pseudo-F statistic, those who were in the lowest quartiles had nearly three times greater risk of developing Parkinson disease [ 9 ]. Risk of dementia or mild cognitive impairment have also been associated with decreased amplitude or delayed acrophase [ 10 , 11 ]. Metrics of RAR irregularity such as decreased interdaily stability (IS, day-to-day stability of RAR) and increased intradaily variability (IV, fragmentation of RAR) have been linked with increased risk of cardiometabolic disorders [ 12 ], neurodegenerative diseases [ 3 , 13 ], and mortality [ 14 – 16 ], thus underscoring the critical role of RAR for human health.…”

Gamma Frequency Sensory Stimulation in Probable Mild Alzheimer’s Dementia Patients: Results of a Preliminary Clinical Trial

“…Prospective studies of circadian rhythms demonstrate reduced stability and increased fragmentation with age, these changes accelerate with diagnosis of MCI or AD and fasten the transition between the two (49). Critical biochemical and behavioral changes appear to work bi-directionally between sleep and neurodegeneration, although the precise temporal dynamics are unknown (50).…”

Associations of actigraphic sleep and circadian rest/activity rhythms with cognition in the early phase of Alzheimer’s disease

“…Prior studies, using standard nonparametric RAR measures, have reported altered RARs among older adults across the spectrum of AD. Overall, such work has shown that older adults exhibit reduced rhythm amplitude, and less stable, more fragmented rhythms, that become increasingly abnormal among those with MCI and after the onset of dementia [ 27 ]. These metrics do not, however, provide information about any shifts that may occur in the temporal details of the 24-hour circadian profile.…”