Amyloid biomarkers track sleep spindle changes in cognitively healthy older adults

Sleep disturbances are among the most common complaints in Alzheimer’s disease, and a growing body of evidence suggests the relationship runs in both directions. A meta-analysis of 27 observational studies found that people with sleep problems had a higher risk of Alzheimer’s disease, cognitive impairment, and preclinical disease, while polysomnographic reviews show that patients display reduced total sleep time, sleep efficiency, slow wave sleep, and REM sleep compared with healthy controls. What has remained unclear is whether blood-based Alzheimer’s biomarkers in people without dementia are already linked to measurable features of their sleep.

A new study addressed this question in 40 cognitively unimpaired adults aged 55 to 75 years, who spent three experimental nights in a sleep laboratory one week apart. The analysis used only nights without intervention from a larger randomized, sham-controlled cross-over trial investigating low-frequency magnetic fields. Participants were free of sleep disorders and physical or mental illness, and blood samples were collected at their usual bedtime and within the first hour after awakening. Plasma concentrations of amyloid-beta 40, amyloid-beta 42, their ratio, total tau, p-tau181, and p-tau217 were quantified using SIMOA technology, with available data for 35 to 40 participants depending on the marker.

Sleep was recorded with the gold standard of polysomnography, yielding 25 macrostructure parameters covering sleep continuity, latencies, stage distribution, awakenings, and stage shifts. Microstructure was assessed through sleep spindles, analyzed frontally for slow spindles at 11 to 13 Hz and parietally for fast spindles at 13 to 16 Hz, and through EEG spectral power from 0.5 to 19.75 Hz across delta, theta, alpha, beta, and spindle frequency bands. Because the analyses were exploratory, no adjustments for multiple comparisons were performed, and findings were interpreted accordingly.

On the subjective level, longer perceived wake duration was associated with higher morning total tau and a larger overnight increase, while an overnight rise in amyloid-beta 42 and a higher morning amyloid-beta 42/40 ratio accompanied less perceived wake. Notably, higher amyloid levels predicted longer perceived sleep latency, but this association disappeared once age, sex, body mass index, and evening biomarker concentrations were controlled, and it did not match the polysomnographically measured latency. In contrast, the subjective wake findings aligned with objective wake after sleep onset and persisted in the regression models.

Sleep architecture showed a tau-dominated pattern. Higher evening concentrations of total tau and p-tau181 were associated with less stage N3 sleep, and the association for total tau remained significant after adjustment for confounders. Indicators of sleep instability, such as a higher number of stage shifts, were linked to lower amyloid-beta 42/40 ratios, and more wake during the night correlated with higher morning total tau and larger overnight tau changes. The number of awakenings was largely unrelated to biomarker concentrations.

The most consistent relationships emerged for sleep spindles. The duration and density of frontal spindles were negatively correlated with amyloid-beta 42 and amyloid-beta 40 across stages N2, N3, and NREM sleep, meaning higher amyloid concentrations accompanied shorter and fewer spindles, and these associations largely persisted after controlling for age, sex, and BMI. Parietal spindle frequency, by contrast, was partly positively correlated with amyloid-beta 42 and the amyloid-beta 42/40 ratio. Spindle amplitude showed only isolated associations, and overnight biomarker changes correlated with spindle duration and density exclusively for tau markers, none of which survived confounder adjustment.

EEG power spectra revealed a complementary picture. Evening and morning amyloid concentrations showed consistent negative correlations with alpha, beta, and spindle-band power, mainly at frontal sites and across all sleep stages except REM. Tau correlations were largely inconsistent, with the sole notable finding being a negative association between evening p-tau181 and frontal theta power during REM sleep, which was no longer significant once sex was controlled. During stage N3, overnight changes in amyloid-beta 42 correlated positively with power across nearly all frequency bands, primarily at occipital electrodes.

The authors urge caution in interpreting overnight biomarker changes as evidence of brain clearance. Evening-to-morning differences in peripheral concentrations reflect the net result of central efflux, peripheral production, hepatic and renal elimination, and posture- and hydration-related shifts in plasma volume. Plasma amyloid-beta also follows a diurnal profile, with within-day variation reaching roughly 14 to 16 percent, and the amyloid-beta 42/40 ratio is considerably more stable than absolute values. Because the design included neither paired CSF sampling nor amyloid or tau PET nor direct measures of glymphatic function, the reported associations should be regarded as correlative and hypothesis-generating rather than evidence of altered central clearance.

Nevertheless, the persistence of the spindle and EEG findings after adjustment for age, sex, and BMI suggests they are not readily explained by these confounders, and they align with previous work linking reduced spindle density and duration to Alzheimer’s pathology in mild cognitive impairment and to CSF biomarkers in healthy elderly individuals. The study is, to the authors’ knowledge, the first to directly assess evening biomarker effects on subsequent sleep, sleep effects on morning biomarkers, and overnight biomarker changes against full polysomnography. Given the small sample, cross-sectional design, and exploratory statistics, replication in larger longitudinal cohorts with multimodal biomarker assessments and repeated sleep and cognitive testing will be needed before sleep spindle metrics can be considered early, non-invasive markers of Alzheimer’s-related biological processes.

Subject of Research: Neuroscience

Article Title: Associations Between Biomarkers of Alzheimer's Disease and Sleep in Cognitively Unimpaired Older Adults

Article References: Sauter, C., Dorn, H., Hellmann‐Regen, J., Bueno‐Lopez, A., van Ginneken, V., & Danker‐Hopfe, H. (2026). Associations Between Biomarkers of Alzheimer's Disease and Sleep in Cognitively Unimpaired Older Adults. Annals of Clinical and Translational Neurology, Article acn3.70562. https://doi.org/10.1002/acn3.70562

Image Credits: AI Generated

DOI: 10.1002/acn3.70562

Keywords: Alzheimer's disease, sleep, amyloid-beta, tau, polysomnography, sleep spindles, EEG, biomarkers, Associations, Between, Alzheimer's, Disease