Gaël Chételat

• PhD
• Research Director at Unité Inserm U1077

Introduction Allostatic load (AL) is a composite score of progressive physiological dysregulations in response to long-term exposure to everyday stress. Despite growing interest, limited research has focused on links with cerebral and cognitive aspects of aging and with markers sensitive to Alzheimer’s disease (AD) in a healthy elderly population a...

INTRODUCTION Specific features of subjective cognitive decline (SCD‐plus) have been proposed to indicate an increased risk of preclinical Alzheimer's disease (AD). However, few studies have examined how these features relate to AD biomarkers in cognitively unimpaired (CU) older adults. METHODS Meta‐analyses were performed using cross‐sectional dat...

Background and objectives: Lifestyle behaviors, including engagement in complex mental activities, have been associated with dementia risk and neuroimaging markers of aging and Alzheimer disease. However, the life period(s) at which lifestyle factors have the greatest influence on brain health remains unclear. Our objective was to determine the re...

Curing Alzheimer’s disease remains hampered by an incomplete understanding of its pathophysiology and progression. Exploring dysfunction in medial temporal lobe networks, particularly the anterior-temporal (AT) and posterior-medial (PM) systems, may provide key insights, as these networks exhibit functional connectivity alterations along the entire...

Background Despite evidence that sex can modulate Alzheimer’s disease (AD) risk, whether risk factors are similarly related to AD markers in women and men remains largely unexplored. We aimed to assess how a combination of potentially modifiable risk factors are associated with cognitive and pathological markers of AD in older women and men. Metho...

Background Locus coeruleus (LC) imaging using neuromelanin‐sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer’s Disease (AD). Although automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on a single template built in a standardized space and/...

Background Education has been associated with reserve mechanisms and lower dementia risk, but the literature shows inconsistent results on the association between education and brain outcomes across the lifespan. Considering that both dementia risk and education are likely to differ between sexes, our study aims at understanding the association bet...

Background Despite evidence that sex can modulate Alzheimer’s disease (AD) risk, whether risk factors are similarly related to AD markers in women and men remains largely unexplored. We aimed to assess how a combination of potentially modifiable risk factors are associated with cognitive and pathological markers of AD in older women and men. Metho...

Background Increased stress, a proposed risk factor for Alzheimer’s disease (AD), is associated with increased brain and cognitive vulnerabilities in older populations, which may be different in women and men. Objective To examine cross‐sectional associations between circulating stress hormones (epinephrine, norepinephrine, cortisol, dehydroepiand...

Background Locus coeruleus (LC) imaging using neuromelanin‐sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer’s Disease (AD). Although automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on a single template built in a standardized space and/...

Background Education has been associated with reserve mechanisms and lower dementia risk, but the literature shows inconsistent results on the association between education and brain outcomes across the lifespan. Considering that both dementia risk and education are likely to differ between sexes, our study aims at understanding the association bet...

White matter hyperintensities (WMH) are highly prevalent in aging and Alzheimer’s disease (AD) and typically attributed to vascular damage and cerebral small vessel disease. Yet, several lines of evidence from the literature emphasize the heterogeneity in the mechanisms leading to WMH, notably in AD, suggesting that WMH may be partly attributable t...

Background:Locus coeruleus (LC) imaging using neuromelanin-sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer's Disease (AD) and Parkinson's Disease (PD). Although semi or fully automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on a single...

Background: Subclinical depressive symptoms increase the risk of developing Alzheimer's disease (AD). The neurobiological mechanisms underlying this link may involve stress system dysfunction, notably related to the hippocampus which is particularly sensitive to AD. We aimed to investigate the links between blood stress markers and changes in brai...

Four important imaging biomarkers of Alzheimer’s disease, namely grey matter atrophy, glucose hypometabolism and amyloid-β and tau deposition, follow stereotypical spatial distributions shaped by the brain network of structural and functional connections. In this case-control study, we combined several predictors reflecting various possible mechani...

Background In cognitively unimpaired (CU) older adults, the presence of a subjective cognitive decline (SCD) combined with evidence of abnormal b‐amyloid (Ab) is proposed as stage 2 of Alzheimer’s disease (AD) by the NIA‐AA framework (Jack et al., 2018). However, the associations found between SCD and preclinical AD are inconsistent across studies,...

Background: Accumulation of critically short telomeres (CST) is implicated in decreased tissular regenerative capacity and increased susceptibility to degenerative diseases such as Alzheimer's disease (AD). Telomere shortening has also been associated with age-related brain changes. However, it remains unclear whether CST accumulation is directly a...

Background Increased stress is a proposed risk factor for Alzheimer’s disease (AD). We examined cross-sectional associations between circulating stress biomarkers and multimodal measures of brain health and cognition susceptible to AD in older adults and sex-specific subgroups. Methods Baseline data from 132 cognitively unimpaired participants wit...

Episodic memory consolidation relies on the functional specialization of brain networks and sleep quality, both of which are affected by aging. Functional connectivity during wakefulness is crucial to support the integration of newly acquired information into memory networks. Additionally, the temporal dynamics of sleep spindles facilitates overnig...

Meditation is a mental training approach that can improve mental health and well-being in aging. Yet the underlying mechanisms remain unknown. The Medit-Ageing model stipulates that three mechanisms — attentional, constructive, and deconstructive — upregulate positive psycho-affective factors and downregulate negative ones. To test this hypothesis,...

Background Cardiovascular risk factors represent an important health issue in older adults. Previous findings suggest that meditation training could have a positive impact on these risk factors. The objective of this study was to investigate the effects of an 18-month meditation-based intervention on cardiovascular health. Methods Age-Well was a r...

Emerging evidence suggests that repetitive negative thinking (RNT; i.e., worry and ruminative brooding) is associated with biomarkers of Alzheimer’s disease. Given that women have a greater risk of many neurodegenerative diseases, this study investigated whether worry and brooding are associated with general neurodegeneration and whether associatio...

Understanding the factors that predict why some individuals perceive to respond more to meditation training than others could impact the development, efficacy, adherence levels, and implementation of meditation-based interventions. We investigated individual-level variables associated with self- and teacher-perceived responsiveness to longer-term m...

Meditation is a family of ancient and contemporary contemplative mind-body practices that can modulate psychological processes, awareness, and mental states. Over the last 40 years, clinical science has manualised meditation practices and designed various meditation interventions (MIs), that have shown therapeutic efficacy for disorders including d...

Background Shorter telomeres are associated with increased risk of cognitive decline and age-related diseases. Developing interventions to promote healthy aging by preserving telomere integrity is of paramount importance. Here, we investigated the effect of an 18-month meditation intervention on telomere length (TL) measures in older people without...

The COVID-19 pandemic significantly challenged mental health of populations worldwide. We aimed to assess changes in mental health of cognitively unimpaired (CU) older adults with pre-existing subclinical depressive symptoms during pandemic-related confinements, and the factors that could modulate these changes. CU older adults with (DepS, n=53) an...

BACKGROUND: Subclinical depressive symptoms increase the risk of developing Alzheimer’s disease (AD). The neurobiological mechanisms underlying this link may involve stress system dysfunction, notably related to the hippocampus which is particularly sensitive to AD. We aimed to investigate the links between blood stress markers and changes in brain...

Background and objectives: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequ...

Breast-cancer (BC) patients (PT) frequently report memory problems pre-and post-cancer treatments that are not always corroborated by memory tests. We hypothesized that self-reported problems actually coincide with structural brain changes and that the discrepancy partly stems from BC-related distressed self-image and stress that alter arousal at m...

Aging is associated with cognitive changes, even in the absence of brain pathology. This study aimed to determine if meditation training, by comparison to active and passive control groups, is linked to changes in the perception of cognitive functioning in older adults. One hundred thirty-four healthy older participants from the Age-Well Randomized...

Introduction Mental health conditions are associated with cognition and physical function in older adults. We examined whether worry and ruminative brooding, key symptoms of certain mental health conditions, are related to subjective and/or objective measures of cognitive and physical (cardiovascular) health. Methods We used baseline data from 282...

Objective Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non‐invasively and identify the determ...

Emerging evidence suggests that Repetitive Negative Thinking (RNT; i.e., worry and ruminative brooding) is associated with biomarkers of Alzheimer’s disease. However, it is neither known whether RNT may be a marker of neurodegenerative disease more generally, nor the mechanism through which RNT may act. Given that women have greater risk of many ne...

Meditation is a family of ancient and contemporary contemplative mind-body practices that can modulate psychological processes, awareness, and mental states. Over the last 40 years, clinical science has manualised meditation practices and designed various meditation interventions (MIs), that have shown therapeutic efficacy for disorders including d...

INTRODUCTION Older adults experiencing subjective cognitive decline (SCD) have a higher risk of dementia. Reducing this risk through behavioral interventions, which can increase emotional well‐being (mindfulness and compassion) and physical activity, is crucial in SCD. METHODS SCD‐Well is a multicenter, observer‐blind, randomized, controlled, supe...

Objective Poor sleep and high levels of repetitive negative thinking (RNT), including future-directed (ie, worry) and past-directed (ie, brooding) negative thoughts, have been associated with markers of dementia risk. The relationship between RNT and sleep health in older adults is unknown. This study aimed to investigate this association and its s...

Importance Lifestyle factors have been associated with dementia risk and neuroimaging markers of ageing and Alzheimer’s Disease (AD), but the period at which they have the greatest influence remains unclear. Objective To determine the relative influence of lifestyle at different life periods on older adults’ brain health. Design, Setting, and Par...

Study objectives: In aging, reduced delta power (0.5-4 Hz) during N2 and N3 sleep has been associated with gray matter (GM) atrophy and hypometabolism within frontal regions. Some studies have also reported associations between N2-N3 sleep delta power in specific sub-bands and amyloid pathology. Our objective was to better understand the relations...

Background Increasing evidence suggests that lifestyle factors are related to cerebral markers of aging and Alzheimer’s disease (AD) in older individuals. However, most studies addressed the association between current lifestyle and neuroimaging, providing little information on the relative effect of lifestyle at different life periods on older adu...

Background Little is known about the genetic factors and downstream molecular pathways determining individual variability in fluid and imaging biomarkers associated with Alzheimer’s disease(AD). We studied polygenic risk scores (PRS) and pathway‐specific PRS in relationship with AD fluid and imaging biomarkers, in non‐demented individuals from the...

Background The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined. Method We included 1592 non‐demented participants from EPAD‐LCS ( Table‐1 ). Linear models were used to study associations between the Framingham score (FRS) and CSF‐...

Background Recent evidence in Alzheimer’s diseases suggests that early dysfunction of emotional processing may precede the onset of cognitive decline and dementia. Altered functional brain connectivity patterns also occur along with other brain changes many years before clinical AD symptoms. Method We combined baseline multimodal neuroimaging data...

Background The medial temporal lobe is extensively connected to the whole brain through two functional networks: the anterior‐temporal (AT) and posterior‐medial (PM) systems. While both increased and decreased functional connectivity (FC) have been reported in Alzheimer’s disease (AD), the specific changes in each network and their clinical relevan...

Background Telomeres (protective chromosomal ends) gradually shorten over the lifespan and have been associated with the development of age‐related diseases such as Alzheimer’s disease (AD). Most studies use median telomere length as a biomarker of cellular aging, but their dysfunction is rather reflected by the load of short telomere. No study to...

Background Positive and negative psychological factors represent pertinent moderators of relative risk and protection for cognitive decline and dementia. For example, repetitive negative thinking has been associated with accelerated cognitive decline and AD pathology ¹ , whereas self‐reflection and purpose in life have been related to better cognit...

Background Subclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stre...

Background Cross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progre...

Background Non‐pharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. We investigated the effects of 18‐months meditation or non‐native language training versus no intervention on cognition in older adults. Method Age‐Well was an observer‐blind, randomised, controlled clinical trial wit...

Background Little is known about the genetic factors and downstream molecular pathways determining individual variability in fluid and imaging biomarkers associated with Alzheimer’s disease(AD). We studied polygenic risk scores (PRS) and pathway‐specific PRS in relationship with AD fluid and imaging biomarkers, in non‐demented individuals from the...

Background Cross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progre...

Background Telomeres (protective chromosomal ends) gradually shorten over the lifespan and have been associated with the development of age‐related diseases such as Alzheimer’s disease (AD). Most studies use median telomere length as a biomarker of cellular aging, but their dysfunction is rather reflected by the load of short telomere. No study to...

Background Increasing evidence suggests that lifestyle factors are related to cerebral markers of aging and Alzheimer’s disease (AD) in older individuals. However, most studies addressed the association between current lifestyle and neuroimaging, providing little information on the relative effect of lifestyle at different life periods on older adu...

Background The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined. Method We included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß...

Background Subclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stre...

Objectives Older adults with subjective cognitive decline (SCD) recruited from memory clinics have an increased risk of developing dementia and regularly experience reduced psychological well-being related to memory concerns and fear of dementia. Research on improving well-being in SCD is limited and lacks non-pharmacological approaches. We investi...

Short mindfulness-based interventions have gained traction in research due to their positive impact on well-being, cognition, and clinical symptoms across various settings. However, these short-term trainings are viewed as preliminary steps within a more extensive transformative path, presumably leading to long-lasting trait changes. Despite this,...

Objectives As the world population is ageing, it is vital to understand how older adults can maintain and deepen their psychological well-being as they are confronted with the unique challenges of ageing in a complex world. Theoretical work has highlighted the promising role of intentional mental training such as meditation practice for enhancing h...

Curing Alzheimer's disease (AD) remains hampered by an incomplete understanding of its pathophysiology and progression. Dysfunction within medial temporal lobe networks may provide key insights, as AD proteins seem to propagate specifically through the anterior-temporal (AT) and posterior-medial (PM) systems. Using monocentric longitudinal data fro...

Sleep, especially slow wave sleep (SWS), is essential for cognitive functioning and is reduced in aging. The impact of sleep quality on cognition is variable, especially in aging. Cognitive reserve (CR) may be an important modulator of these effects. We aimed at investigating this question to better identify individuals in whom sleep disturbances m...

During the past decade, cognitive neuroscience has been calling for population diversity to address the challenge of validity and generalizability, ushering in a new era of population neuroscience. The developing Chinese Color Nest Project (devCCNP, 2013–2022), the first ten-year stage of the lifespan CCNP (2013–2032), is a two-stages project focus...

Importance: Nonpharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. Objective: To investigate the effects of 18 months' meditation training and 18 months' non-native language training on cognition in older adults. Design, setting, and participants: This study was a secondary analy...

Background APOE4 is the main genetic risk factor for Alzheimer’s disease (AD). Recent findings suggest that lifestyle factors could modulate the association between APOE4 and cognitive impairment and/or dementia risk. However, a comprehensive assessment of the interactions between lifestyle and APOE4 status on neuroimaging and cognitive markers of...

Background Allostatic load (AL) is a cumulative measure of dysregulations across multiple physiological systems of the body occurring over time. AL was originally developed to explain how chronic stress damages physiologic systems and accelerates aging. Studies exploring the relationship between AL and brain health in older adults using a multimoda...

Background and objectives Sleep-disordered breathing (SDB) has been related to amyloid deposition and increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB seve...

Objective: Self-perceived cognitive functioning, considered highly relevant in the context of aging and dementia, is assessed in numerous ways-hindering the comparison of findings across studies and settings. Therefore, the present study aimed to link item-level self-report questionnaire data from international aging studies. Method: We harmoniz...

Background: Alzheimer’s disease (AD) and Korsakoff’s syndrome (KS) are two major neurocognitive disorders characterized by amnesia but AD is degenerative while KS is not. The objective is to compare regional volume deficits within the Papez circuit in AD and KS, considering AD progression. Methods: 18 KS patients, 40 AD patients (20 with Moderate A...

Background and objectives Studies are sparse regarding the association between the informant-reported subjective memory decline (informant-report) and Alzheimer’s disease (AD) biomarkers. This study thus aimed at determining the clinical relevance of the informant-report throughout the AD clinical continuum, by assessing its specific relationships...

Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures fro...

White matter hyperintensities (WMH), frequently seen in older adults, are usually considered vascular lesions, and participate in the vascular contribution to cognitive impairment and dementia. However, emerging evidence highlights the heterogeneity of WMH pathophysiology, suggesting that non-vascular mechanisms could also be involved, notably in A...

Medial temporal lobe (MTL) subregions are differentially affected in Alzheimer's disease (AD), with a specific involvement of the entorhinal cortex (ERC), perirhinal cortex and hippocampal cornu ammonis (CA)1. While amyloid (Aβ) and APOEε4 are respectively the first molecular change and the main genetic risk factor in AD, their links with MTL atrop...

Amyloid-β accumulation starts in highly connected brain regions and is associated with functional connectivity alterations in the early stages of Alzheimer’s disease. This regional vulnerability is related to the high neuronal activity and strong fluctuations typical of these regions. Recently, dynamic functional connectivity was introduced to inve...

Observational population studies indicate that prevention of dementia and cognitive decline is being accomplished, possibly as an unintended result of better vascular prevention and healthier lifestyles. Population aging in the coming decades requires deliberate efforts to further decrease its prevalence and societal burden. Increasing evidence sup...

Objectives Aging people experience a slight decrease in their cognitive efficiency, even in the absence of brain pathology. Concurrently, several studies have reported positive effects of meditation practice on older adults’ cognitive functioning. This study aimed to assess if dispositional mindfulness (or more generally trait meditation capacities...

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, grey matter volume and p...

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-emot...

Early amyloid deposition results in functional and structural brain alterations in predementia stages of Alzheimer's disease (AD). However, how early functional and structural brain changes are related to each other remains unclear. Investigating the simultaneous disruptions of functional‐structural brain features within individuals in relation to...

The medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks which are particularly affected in Alzheimer’s disease (AD): the anterior‐temporal (AT) and posterior‐medial (PM) systems. As the specific and respective effects of age and sex on the functional integrity of these networks are still largel...

Early amyloid deposition results in functional and structural brain alterations in predementia stages of Alzheimer's disease (AD). However, how early functional and structural brain changes are related to each other remains unclear. Investigating the simultaneous disruptions of functional‐structural brain features within individuals in relation to...

In preclinical Alzheimer’s disease (AD), amyloid accumulates in highly‐functionally connected brain regions. This selective vulnerability is related to the high neuronal fluctuations, typical of these regions. Dynamic functional connectivity (FC) was introduced to investigate network organization over time, with high network variations indicating r...

In preclinical Alzheimer’s disease (AD), amyloid accumulates in highly‐functionally connected brain regions. This selective vulnerability is related to the high neuronal fluctuations, typical of these regions. Dynamic functional connectivity (FC) was introduced to investigate network organization over time, with high network variations indicating r...

Allostatic load (AL) is a cumulative measure of dysregulations across multiple physiological systems of the body occurring over time. AL was originally developed to explain how chronic stress damages physiologic systems and accelerates aging. Studies exploring the relationship between AL and brain health in older adults using a multimodal approach...

The medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks which are particularly affected in Alzheimer’s disease (AD): the anterior‐temporal (AT) and posterior‐medial (PM) systems. As the specific and respective effects of age and sex on the functional integrity of these networks are still largel...

APOE4 is the main genetic risk factor for Alzheimer’s disease (AD). Recent findings suggest that lifestyle factors could modulate the association between APOE4 and cognitive impairment and/or dementia risk. However, a comprehensive assessment of the interactions between lifestyle and APOE4 status on neuroimaging and cognitive markers of aging and A...

Brain‐age can be inferred from structural neuroimaging and compared to chronological age (brain‐age delta), as a marker of accelerated/decelerated biological brain aging. Accelerated biological aging has been found in Alzheimer’s disease (AD), but validation against biomarkers of AD and neurodegeneration is lacking. We studied the association betwe...