ISO peak amplitude was significantly reduced in AD while intrinsic frequency and bandwidth were preserved, suggesting selective weakening of infraslow oscillations in sleep spindle activity as a novel electrophysiological marker linking sleep microarchitecture to AD pathology.
Key Findings
Results
ISO peak amplitude was significantly reduced in AD participants compared to controls.
The analysis extracted ISO peak amplitude, intrinsic frequency, and bandwidth from the sigma-power time-course during NREM sleep EEG
Group differences in ISO peak amplitude were statistically significant between AD participants and controls
Intrinsic frequency and bandwidth of ISO were preserved (not significantly different between groups)
This selective weakening of ISO amplitude, while other ISO parameters remained intact, was described as consistent with locus coeruleus dysfunction
Results
ISO peak amplitude showed a trend-level association with the plasma biomarker Aβ42/40.
Aβ42/40 ratio is a plasma biomarker associated with amyloid pathology in Alzheimer's disease
The association between ISO peak amplitude and Aβ42/40 was described as 'trend-level' rather than statistically significant
This association was part of a broader analysis correlating ISO parameters with multiple plasma biomarkers including pTau181, pTau217, NfL, and GFAP
Results
ISO bandwidth was positively associated with neurofilament light chain (NfL) plasma levels.
NfL is a plasma biomarker reflecting neurodegeneration and neuroaxonal damage
The association between ISO bandwidth and NfL was described as a positive correlation
ISO bandwidth also showed trend-level associations with GFAP, a marker of astrocyte activation and neuroinflammation
ISO bandwidth showed trend-level associations with lower verbal memory retention
Results
ISO bandwidth showed trend-level associations with lower verbal memory retention in participants.
Verbal memory retention was assessed as a cognitive outcome measure
The association between ISO bandwidth and verbal memory retention was described as trend-level
This finding suggests a potential link between ISO characteristics and cognitive performance relevant to AD
Background
The authors hypothesize that ISO integrity is a critical link between sleep and Alzheimer's disease, mediated by locus coeruleus and glymphatic dysfunction.
Locus coeruleus (LC) dysfunction has been linked to both AD and ISO in sleep spindle (sigma) activity
Glymphatic dysfunction has similarly been linked to both AD and ISO
Selective weakening of ISO amplitude in AD is described as 'consistent with LC dysfunction and impaired glymphatic cycling'
ISO is proposed as 'a novel mechanism and electrophysiological marker linking sleep microarchitecture to AD pathology'
Methods
The study analyzed NREM sleep EEG data from AD participants and controls, extracting three ISO parameters from the sigma-power time-course.
Data source was non-rapid eye movement (NREM) sleep EEG recordings
Three ISO parameters were extracted: peak amplitude, intrinsic frequency, and bandwidth
These parameters were derived from the sigma-power time-course, reflecting oscillatory dynamics in sleep spindle activity
Plasma biomarkers assessed included Aβ42/40, pTau181, pTau217, NfL, and GFAP
What This Means
This research suggests that a specific type of brain rhythm during sleep — called an infraslow oscillation (ISO) — may be disrupted in people with Alzheimer's disease. These ISOs appear as slow, rhythmic fluctuations in sleep spindle activity (brain waves that occur during deep sleep) and can be measured using EEG. The study found that the strength (amplitude) of these oscillations was significantly reduced in people with Alzheimer's compared to healthy controls, while other characteristics of the rhythm, such as its speed and range, remained largely intact. Importantly, these ISO features also showed statistical trends linking them to blood biomarkers of Alzheimer's-related brain changes, including amyloid buildup and neurodegeneration markers.
The researchers propose that these disrupted sleep rhythms may be connected to two systems known to malfunction in Alzheimer's disease: the locus coeruleus (a brain region involved in regulating alertness and norepinephrine signaling) and the glymphatic system (a waste-clearance system in the brain that is most active during sleep). When these systems fail, the brain may not clean itself efficiently during sleep, potentially accelerating the accumulation of toxic proteins associated with Alzheimer's. The fact that ISO bandwidth was also associated with poorer verbal memory retention adds to the picture that these rhythms may be functionally important for cognition.
This research suggests that infraslow oscillations during sleep could serve as a novel, non-invasive marker for detecting or monitoring Alzheimer's disease-related changes in the brain. If validated in larger studies, measuring ISO characteristics from sleep EEG recordings could eventually complement blood-based biomarkers for assessing Alzheimer's risk or progression, and could point toward sleep-based interventions as a potential avenue for research.
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Grollero D, Gabb V, Blackman J, Heslegrave A, de Vivo L, Coulthard E, et al.. (2026). Are infraslow oscillations the missing link between sleep and Alzheimer's?. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.71525