Lladó, Albert

Abstract Background Sleep disturbances are common in Alzheimer's disease and have been reported in its preclinical stage. A detailed characterization of sleep disruption across the Alzheimer’s disease continuum is required to clarify its role as a potential therapeutic target and to evaluate the utility of sleep-related biomarkers. Methods Sleep architecture was characterized through detailed spectral and temporal analysis of the slow-wave activity using polysomnography across the Alzheimer’s disease continuum . Participants included: cognitively unimpaired individuals without abnormal Alzheimer’s disease biomarkers (n = 30), cognitively unimpaired individuals with abnormal Alzheimer’s disease biomarkers (n = 45), and individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease (n = 41). Associations between slow-wave features and longitudinal cognitive performance were tested in cognitively unimpaired participants. Sex differences were also explored. Results A stepwise increased wake after sleep onset and latency to rapid eye movement sleep was observed, alongside reduced spectral power of slow-wave activity and a progressive flattening of slow-waves across the Alzheimer’s disease continuum in both sexes. In cognitively unimpaired individuals, higher slow-wave slope and greater peak-to-peak amplitude were associated with better cognitive trajectories over time. Conclusions Sleep macro- and microarchitecture are altered early and progressively deteriorate across the Alzheimer’s disease continuum . Slow-wave features relate to cognitive trajectories in preclinical Alzheimer’s disease, with exploratory analyses suggesting stronger associations in men. These findings support slow-wave morphology as a candidate non-invasive marker for future sleep-based intervention studies.

Abstract INTRODUCTION Sleep disruption, particularly loss of slow‐wave sleep (SWS), is common in Alzheimer's disease (AD), but its neurobiological underpinnings remain unclear. We investigated whether locus coeruleus (LC) integrity relates to SWS across the AD continuum and whether sex and perivascular spaces (PVSs) modify these associations. METHODS In a cohort (11 controls, 30 mild cognitive impairment, 17 AD dementia) we combined overnight polysomnography with LC‐sensitive magnetic resonance imaging of the LC, basal ganglia and centrum semiovale PVS ratings, and cerebrospinal fluid noradrenaline. Multivariable linear regression adjusted for demographics, disease stage, and medication use. RESULTS Higher LC integrity was associated with greater slow‐wave activity and slow oscillation power, with stronger effects in females. Basal ganglia PVS burden was related to lower SWS spectral power, whereas noradrenaline levels were not associated with sleep. DISCUSSION LC integrity, sex, and PVS burden show associations with SWS alterations in aging and AD, supporting restorative sleep as a potential therapeutic target.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

BackgroundThe cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.MethodsThe program is open for laboratories using commercially available kits for Aβ, T‐tau, or P‐tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples.ResultsForty laboratories participated. Twenty‐six used INNOTEST enzyme‐linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO‐BIA AlzBio3 kit (both measure Aβ‐(1‐42), P‐tau(181P), and T‐tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN‐42, AβN‐40, and AβN‐38) or T‐tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within‐laboratory precisions differed considerably between biomarkers within individual laboratories.ConclusionsMeasurements of CSF AD biomarkers show large between‐laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.