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International audience; Objective: Rapid eye movement (REM) sleep is markedly altered in Alzheimer's disease (AD), and its reduction in older populations is associated with AD risk. However, little is known about the underlying brain mechanisms. Our objective was to investigate the relationships between REM sleep integrity and amyloid deposition, gray matter volume, and perfusion in aging.Methods: We included 121 cognitively unimpaired older adults (76 women, mean age 68.96 ± 3.82 years), who underwent a polysomnography, T1-weighted magnetic resonance imaging, early and late Florbetapir positron emission tomography scans to evaluate gray matter volume, perfusion, and amyloid deposition. We computed indices reflecting REM sleep macro- and microstructural integrity (ie, normalized electroencephalographic spectral power values). Voxel-wise multiple regression analyses were conducted between REM sleep indices and neuroimaging data, controlling for age, sex, education, the apnea-hypopnea index, and the apolipoprotein E ε4 status.Results: Lower perfusion in frontal, anterior and posterior cingulate, and precuneus areas was associated with decreased delta power and electroencephalographic slowing (slow/fast frequencies ratio), and increased alpha and beta power. To a lower extent, similar results were obtained between gray matter volume and delta, alpha, and beta power. In addition, lower REM sleep theta power was more marginally associated with greater diffuse amyloid deposition and lower gray matter volume in fronto-temporal and parieto-occipital areas.Interpretation: These results suggest that alterations of REM sleep microstructure are associated with greater neurodegeneration and neocortical amyloid deposition in older adults. Further studies are warranted to replicate these findings, and determine whether older adults exhibiting REM sleep alterations are more at risk of cognitive decline and belonging to the Alzheimer's continuum. ANN NEUROL 2023.

Additional file 1. Supplementary materials.

BackgroundOlder individuals with subjective cognitive decline (SCD) perceive that their cognition has declined but do not show objective impairment on neuropsychological tests. Individuals with SCD are at elevated risk of objective cognitive decline and incident dementia. Non-pharmacological interventions (including mindfulness-based and health self-management approaches) are a potential strategy to maintain or improve cognition in SCD, which may ultimately reduce dementia risk.MethodsThis study utilized data from the SCD-Well randomized controlled trial. One hundred forty-seven older adults with SCD (MAge= 72.7 years; 64% female) were recruited from memory clinics in four European countries and randomized to one of two group-based, 8-week interventions: a Caring Mindfulness-based Approach for Seniors (CMBAS) or a health self-management program (HSMP). Participants were assessed at baseline, post-intervention (week 8), and at 6-month follow-up (week 24) using a range of cognitive tests. From these tests, three composites were derived—an “abridged” Preclinical Alzheimer’s Cognitive Composite 5 (PACC5Abridged), an attention composite, and an executive function composite. Both per-protocol and intention-to-treat analyses were performed. Linear mixed models evaluated the change in outcomes between and within arms and adjusted for covariates and cognitive retest effects. Sensitivity models repeated the per-protocol analyses for participants who attended ≥ 4 intervention sessions.ResultsAcross all cognitive composites, there were no significant time-by-trial arm interactions and no measurable cognitive retest effects; sensitivity analyses supported these results. Improvements, however, were observed within both trial arms on the PACC5Abridgedfrom baseline to follow-up (Δ [95% confidence interval]: CMBAS = 0.34 [0.19, 0.48]; HSMP = 0.30 [0.15, 0.44]). There was weaker evidence of an improvement in attention but no effects on executive function.ConclusionsTwo non-pharmacological interventions conferred small, non-differing improvements to a global cognitive composite sensitive to amyloid-beta-related decline. There was weaker evidence of an effect on attention, and no evidence of an effect on executive function. Importantly, observed improvements were maintained beyond the end of the interventions. Improving cognition is an important step toward dementia prevention, and future research is needed to delineate the mechanisms of action of these interventions and to utilize clinical endpoints (i.e., progression to mild cognitive impairment or dementia).Trial registrationClinicalTrials.gov, NCT03005652.

Medial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) (n = 46) and amyloid-positive (Aβ+) (n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) (n = 33) and AD (n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition.

One of the major challenges for society is to keep the growing population of elders in good health by protecting them from cognitive decline and the risk of developing Alzheimer's disease. Maintaining quality of life and sleep, which decline with age, is also essential to achieve healthy aging. The main objective of this thesis was to contribute to a better understanding of the factors and mechanisms associated with quality of life, with a particular interest for cognitive reserve – a compensatory mechanism that promotes better cognitive functioning – and age-related sleep changes. Our results show that perceived physical health is positively associated with the integrity of several brain areas, known to be vulnerable to the effects of age. In addition, cognitive reserve, measured using the Lifetime of Experiences Questionnaire (LEQ) – a questionnaire that we also validated in several languages – moderates the negative effects of age-related sleep changes, and specially the decrease of slow wave sleep, on executive functions and episodic memory. Thus, preventive and / or interventional strategies which aim to improve quality of life and sleep or to increase cognitive reserve, throughout life, would promote successful aging., L’un des défis majeurs de la société est de maintenir la population croissante de personnes âgées en bonne santé en les préservant du déclin cognitif et des risques de développer une maladie d’Alzheimer. Maintenir la qualité de vie et du sommeil, qui diminuent avec l’âge, est également essentiel pour atteindre ce vieillissement en bonne santé. L’objectif principal de cette thèse était de contribuer à une meilleure compréhension des facteurs et des mécanismes associés à la qualité de vie chez le sujet âgé, avec un intérêt particulier pour la réserve cognitive – mécanisme compensatoire qui favorise un meilleur fonctionnement cognitif – et les modifications du sommeil. Nos résultats montrent que la santé physique perçue est positivement associée à l’intégrité de régions cérébrales qui sont particulièrement sensibles aux effets de l’âge. De plus, la réserve cognitive, mesurée à l’aide du Questionnaire sur les Expériences de la Vie (QEV ou LEQ) – questionnaire que nous avons également validé en plusieurs langues – modère les effets négatifs des troubles du sommeil, et plus particulièrement la réduction du sommeil lent profond, sur les performances exécutives et de mémoire épisodique. Ainsi, des stratégies préventives et/ou interventionnelles qui visent à améliorer la qualité de vie et du sommeil ou à augmenter la réserve cognitive tout au long de la vie permettraient de promouvoir le vieillissement en bonne santé.

One of the major challenges for society is to keep the growing population of elders in good health by protecting them from cognitive decline and the risk of developing Alzheimer's disease. Maintaining quality of life and sleep, which decline with age, is also essential to achieve healthy aging. The main objective of this thesis was to contribute to a better understanding of the factors and mechanisms associated with quality of life, with a particular interest for cognitive reserve – a compensatory mechanism that promotes better cognitive functioning – and age-related sleep changes. Our results show that perceived physical health is positively associated with the integrity of several brain areas, known to be vulnerable to the effects of age. In addition, cognitive reserve, measured using the Lifetime of Experiences Questionnaire (LEQ) – a questionnaire that we also validated in several languages – moderates the negative effects of age-related sleep changes, and specially the decrease of slow wave sleep, on executive functions and episodic memory. Thus, preventive and / or interventional strategies which aim to improve quality of life and sleep or to increase cognitive reserve, throughout life, would promote successful aging., L’un des défis majeurs de la société est de maintenir la population croissante de personnes âgées en bonne santé en les préservant du déclin cognitif et des risques de développer une maladie d’Alzheimer. Maintenir la qualité de vie et du sommeil, qui diminuent avec l’âge, est également essentiel pour atteindre ce vieillissement en bonne santé. L’objectif principal de cette thèse était de contribuer à une meilleure compréhension des facteurs et des mécanismes associés à la qualité de vie chez le sujet âgé, avec un intérêt particulier pour la réserve cognitive – mécanisme compensatoire qui favorise un meilleur fonctionnement cognitif – et les modifications du sommeil. Nos résultats montrent que la santé physique perçue est positivement associée à l’intégrité de régions cérébrales qui sont particulièrement sensibles aux effets de l’âge. De plus, la réserve cognitive, mesurée à l’aide du Questionnaire sur les Expériences de la Vie (QEV ou LEQ) – questionnaire que nous avons également validé en plusieurs langues – modère les effets négatifs des troubles du sommeil, et plus particulièrement la réduction du sommeil lent profond, sur les performances exécutives et de mémoire épisodique. Ainsi, des stratégies préventives et/ou interventionnelles qui visent à améliorer la qualité de vie et du sommeil ou à augmenter la réserve cognitive tout au long de la vie permettraient de promouvoir le vieillissement en bonne santé.

Introduction Subjectively experienced cognitive decline in older adults is an indicator of increased risk for dementia and is also associated with increased levels of anxiety symptoms. As anxiety is itself emerging as a risk factor for cognitive decline and dementia, the primary question of the present study is whether an 8-week mindfulness-based intervention can significantly reduce anxiety symptoms in patients with subjective cognitive decline (SCD). The secondary questions pertain to whether such changes extend to other domains of psychological, social, and biological functioning (including cognition, self-regulation, lifestyle, well-being and quality of life, sleep, and selected blood-based biomarkers) associated with mental health, older age, and risk for dementia. Methods SCD-Well is a multicenter, observer-blinded, randomized, controlled, superiority trial, which is part of the Horizon 2020 European Union-funded “Medit-Ageing” project. SCD-Well compares an 8-week mindfulness- and compassion-based intervention specifically adapted for older adults with SCD with a validated 8-week health education program. Participants were recruited from memory clinics in four European sites (Cologne, Germany; London, United Kingdom; Barcelona, Spain; and Lyon, France) and randomized with a 1:1 allocation, stratified by site. Results The primary outcome, change in anxiety symptoms, and secondary outcomes reflecting psychological, cognitive, social, and biological functioning are assessed at baseline, postintervention, and 4 months after the end of the intervention. Discussion The study will provide evidence on whether a mindfulness-based intervention can effect changes in anxiety and other risk factors for cognitive decline and dementia in older adults with SCD and will inform the establishment of intervention strategies targeted at improving mental health in older adults., Highlights • Mindfulness may benefit older adults with subjective cognitive decline (SCD). • SCD-Well compares an 8-week mindfulness intervention to a health education course. • Patients with SCD were recruited from memory clinics in four countries. • Outcomes include anxiety symptoms, psychosocial, cognitive, and biological function. • Results will inform future prevention studies and strategies in SCD.

Nonpharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults.To investigate the effects of 18 months' meditation training and 18 months' non-native language training on cognition in older adults.This study was a secondary analysis of the Age-Well trial, an 18-month, observer-masked, randomized clinical trial with 3 parallel arms. Eligible participants were community-dwelling adults aged 65 years and older residing in Caen, France. Participants were enrolled from November 24, 2016, to March 5, 2018, and randomly assigned (1:1:1) to meditation training, non-native language (English) training, or no intervention arms. Final follow-up was completed on February 6, 2020. Data were analyzed between December 2021 and November 2022.The 18-month meditation and non-native language training interventions were structurally equivalent and included 2-hour weekly group sessions, daily home practice of 20 minutes or longer, and 1 day of more intensive home practice. The no intervention group was instructed not to change their habits and to continue living as usual.Cognition (a prespecified secondary outcome of the Age-Well trial) was assessed preintervention and postintervention via the Preclinical Alzheimer Cognitive Composite 5 (PACC5), and composites assessing episodic memory, executive function, and attention.Among 137 randomized participants, 2 were excluded for not meeting eligibility criteria, leaving 135 (mean [SD] age, 69.3 [3.8] years; 83 female [61%]) eligible for analysis. One participant among the remaining 135 did not complete the trial. In adjusted mixed effects models, no interaction effects were observed between visit and group for PACC5 (F2,131.39 = 2.58; P = .08), episodic memory (F2,131.60 = 2.34; P = .10), executive function (F2,131.26 = 0.89; P = .41), or attention (F2,131.20 = 0.34; P = .79). Results remained substantively unchanged across sensitivity and exploratory analyses.In this secondary analysis of an 18-month randomized trial, meditation and non-native language training did not confer salutary cognitive effects. Although further analyses are needed to explore the effects of these interventions on other relevant outcomes related to aging and well-being, these findings did not support the use of these interventions for enhancing cognition in cognitively healthy older adults.ClinicalTrials.gov Identifier: NCT02977819.

Basic emotional functions seem well preserved in older adults. However, their reactivity to and recovery from socially negative events remain poorly characterized. To address this, we designed a 'task-rest' paradigm in which 182 participants from two independent experiments underwent functional magnetic resonance imaging while exposed to socio-emotional videos. Experiment 1 (N = 55) validated the task in young and older participants and unveiled age-dependent effects on brain activity and connectivity that predominated in resting periods after (rather than during) negative social scenes. Crucially, emotional elicitation potentiated subsequent resting-state connectivity between default mode network and amygdala exclusively in older adults. Experiment 2 replicated these results in a large older adult cohort (N = 127) and additionally showed that emotion-driven changes in posterior default mode network-amygdala connectivity were associated with anxiety, rumination and negative thoughts. These findings uncover the neural dynamics of empathy-related functions in older adults and help understand its relationship to poor social stress recovery.

Importance: Positron emission tomography (PET) biomarkers are the gold standard for detection of Alzheimer amyloid and tau in vivo . Such imaging can identify cognitively unimpaired (CU) individuals who will subsequently develop cognitive impartment (CI). Plasma biomarkers would be more practical than PET or even cerebrospinal fluid (CSF) assays in clinical settings., Objective: Assess the prognostic accuracy of plasma p-tau217 in comparison to CSF and PET biomarkers for predicting the clinical progression from CU to CI., Design: In a cohort of elderly at high risk of developing Alzheimer's dementia (AD), we measured the proportion of CU individuals who developed CI, as predicted by Aβ (A+) and/or tau (T+) biomarker assessment from plasma, CSF, and PET. Results from each method were compared with (A-T-) reference individuals. Data were analyzed from June 2023 to April 2024., Setting: Longitudinal observational cohort., Participants: Some 228 participants from the PREVENT-AD cohort were CU at the time of biomarker assessment and had 1 - 10 years of follow-up. Plasma was available from 215 participants, CSF from 159, and amyloid- and tau-PET from 155. Ninety-three participants had assessment using all three methods (main group of interest). Progression to CI was determined by clinical consensus among physicians and neuropsychologists who were blind to plasma, CSF, PET, and MRI findings, as well as APOE genotype., Exposures: Plasma Aβ 42/40 was measured using IP-MS; CSF Aβ 42/40 using Lumipulse; plasma and CSF p-tau217 using UGOT assay. Aβ-PET employed the 18 F-NAV4694 ligand, and tau-PET used 18 F-flortaucipir., Main Outcome: Prognostic accuracy of plasma, CSF, and PET biomarkers for predicting the development of CI in CU individuals., Results: Cox proportional hazard models indicated a greater progression rate in all A+T+ groups compared to A-T-groups (HR = 6.61 [95% CI = 2.06 - 21.17] for plasma, 3.62 [1.49 - 8.81] for CSF and 9.24 [2.34 - 36.43] for PET). The A-T+ groups were small, but also characterized with individuals who developed CI. Plasma biomarkers identified about five times more T+ than PET., Conclusion and Relevance: Plasma p-tau217 assessment is a practical method for identification of persons who will develop cognitive impairment up to 10 years later., Key Points: Question: Can plasma p-tau217 serve as a prognostic indicator for identifying cognitively unimpaired (CU) individuals at risk of developing cognitive impairments (CI)? Findings: In a longitudinal cohort of CU individuals with a family history of sporadic AD, almost all individuals with abnormal plasma p-tau217 concentrations developed CI within 10 years, regardless of plasma amyloid levels. Similar findings were obtained with CSF p-tau217 and tau-PET. Fluid p-tau217 biomarkers had the main advantage over PET of identifying five times more participants with elevated tau. Meaning: Elevated plasma p-tau217 levels in CU individuals strongly indicate future clinical progression.