Volume 19, Issue 12 p. 5700-5718
RESEARCH ARTICLE
Open Access

Physical activity, biomarkers of brain pathologies and dementia risk: Results from the Memento clinical cohort

Leslie Grasset

Corresponding Author

Leslie Grasset

University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CIC1401-EC, Bordeaux, France

Correspondence

Leslie Grasset, INSERM U1219, University of Bordeaux, 146 rue Léo Saignat, 33077 Bordeaux, France.

E-mail: [email protected]

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Vincent Planche

Vincent Planche

University of Bordeaux, CNRS UMR 5293, Institut des Maladies Neurodégénératives, Centre Mémoire de Ressources et de Recherches, Pôle de Neurosciences Cliniques, CHU de Bordeaux, Bordeaux, France

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Vincent Bouteloup

Vincent Bouteloup

University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CIC1401-EC, Bordeaux, France

Pole de sante publique Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France

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Chabha Azouani

Chabha Azouani

CATI multicentre imaging platform, US52-UAR2031, CEA, ICM, SU, CNRS, INSERM, APHP, Gif-sur-Yvette, France

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Bruno Dubois

Bruno Dubois

IM2A AP-HP INSERM UMR-S975 Groupe Hospitalier Pitié-Salpêtrière Institut de la Mémoire et de la Maladie d'Alzheimer Institut du Cerveau et de la Moelle épinière Sorbonne Université Paris, Paris, France

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Frédéric Blanc

Frédéric Blanc

ICube laboratory, Pôle de Gériatrie, Université de Strasbourg, CNRS, UMR 7357, Fédération de Médecine Translationnelle de Strasbourg, Centre Mémoire de Ressources et de Recherches, Strasbourg, France

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Claire Paquet

Claire Paquet

Université de Paris Cité, Centre de Neurologie Cognitive GHU APHP Nord Hôpital Lariboisière, INSERMU1144, Paris, France

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Renaud David

Renaud David

Department of Old Age Psychiatry, Nice University Hospital, Nice, France

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Catherine Belin

Catherine Belin

Service de Neurologie Hôpital Saint-Louis AP-HP, Paris, France

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Thérèse Jonveaux

Thérèse Jonveaux

Centre Mémoire de Ressources et de Recherche de Lorraine, Service de Neurologie CHRU Nancy, Laboratoire Lorrain de Psychologie et de Neurosciences de la dynamique des comportements 2LPN EA 7489 Université de Lorraine, Nancy, France

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Adrien Julian

Adrien Julian

Service de Neurologie CHU La Milétrie Centre Mémoire de Ressources et de Recherche, Poitiers, France

Centre d'Investigation Clinique CIC1402, Poitiers, France

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Jérémie Pariente

Jérémie Pariente

Department of Neurology, Toulouse University Hospital, Toulouse, France

Toulouse NeuroImaging Center, Universite de Toulouse, Inserm, UPS, Toulouse, France

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Jean-François Mangin

Jean-François Mangin

CATI multicentre imaging platform, US52-UAR2031, CEA, ICM, SU, CNRS, INSERM, APHP, Gif-sur-Yvette, France

Université Paris-Saclay, CEA, CNRS, Neurospin, UMR 9027, Gif-sur-Yvette, France

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Geneviève Chêne

Geneviève Chêne

University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CIC1401-EC, Bordeaux, France

Pole de sante publique Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France

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Carole Dufouil

Carole Dufouil

University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CIC1401-EC, Bordeaux, France

Pole de sante publique Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France

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the Memento Cohort Study Group

the Memento Cohort Study Group

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First published: 08 July 2023
Citations: 1

Geneviève Chêne and Carole Dufouil contributed equally to this study.

Abstract

INTRODUCTION

This study aims to examine whether physical activity moderates the association between biomarkers of brain pathologies and dementia risk.

METHODS

From the Memento cohort, we analyzed 1044 patients with mild cognitive impairment, aged 60 and older. Self-reported physical activity was assessed using the International Physical Activity Questionnaire. Biomarkers of brain pathologies comprised medial temporal lobe atrophy (MTA), white matter lesions, and plasma amyloid beta (Aβ)42/40 and phosphorylated tau181. Association between physical activity and risk of developing dementia over 5 years of follow-up, and interactions with biomarkers of brain pathologies were tested.

RESULTS

Physical activity moderated the association between MTA and plasma Aβ42/40 level and increased dementia risk. Compared to participants with low physical activity, associations of both MTA and plasma Aβ42/40 on dementia risk were attenuated in participants with high physical activity.

DISCUSSION

Although reverse causality cannot be excluded, this work suggests that physical activity may contribute to cognitive reserve.

Highlights

  • Physical activity is an interesting modifiable target for dementia prevention.
  • Physical activity may moderate the impact of brain pathology on dementia risk.
  • Medial temporal lobe atrophy and plasma amyloid beta 42/40 ratio were associated with increased dementia risk especially in those with low level of physical activity.

1 BACKGROUND

With the rapid aging of the population, a growing number of individuals will be at risk of developing neurodegenerative diseases.1 In the absence of effective treatments against dementia, identifying protective factors of cognitive decline that could therefore delay dementia onset is of utmost importance. Physical activity represents an interesting modifiable target for prevention strategies, and intervention could be implemented in the elderly population. Indeed, in addition to its global benefits for health,2-4 a high level of physical activities may lower dementia risk and attenuate cognitive decline, even at older ages.5-8 Interestingly, it has also been shown that higher levels of physical activity are related to better cognitive performance among individuals at higher risk of dementia such as individuals with mild cognitive impairment (MCI).9-11 Therefore, physical activity should also be explored as a potential target for delaying conversion to dementia in symptomatic older persons with MCI.

Brain pathologic changes, such as small vessel disease, Alzheimer's disease (AD) neuropathology (amyloid plaques and neurofibrillary tangles), and brain atrophy can develop decades prior to dementia diagnosis, and accelerate its clinical onset. There is growing evidence that older adults being physically more active may preserve longer their brain health assessed with brain volume, cortical thickness, or functional activity.12-14 A few studies have also reported reduced AD pathology or lower load of cerebrovascular disease with higher physical activity.15-18 However, whether physical activity may contribute to cognitive reserve and modify the negative impact of these brain changes on dementia risk remains unclear, especially for individuals already experiencing some cognitive impairment.19 Cognitive reserve is a concept referring to the ability to maintain adequate cognitive functions despite development of brain pathologies.20 Individuals with higher cognitive reserve may thus be able to compensate for the negative effects of brain pathologies. A factor contributing to cognitive reserve will moderate the impact of brain pathologies on cognitive decline.21 Some studies, mainly among cognitively normal individuals, have reported that physical activity moderates the association between some brain pathologies (AD pathology, cerebrovascular injury, or brain atrophy) and cognitive function or decline, which is consistent with the concept of cognitive reserve.20, 22-27 However, results from some other studies did not support the contribution of physical activity to cognitive reserve.22, 25, 28, 29 Inconsistent findings across studies can be explained by selection biases (various sample sizes, convenience sampling, and different study settings) as well as lack of comparability of selected biomarkers of brain pathologies. Moreover, most previous studies were conducted among cognitively healthy older adults, and whether similar relationships are present in cognitively impaired persons, such as MCI participants, remains uncertain. Evidencing a moderating effect of physical activity on brain pathologies over conversion from MCI to dementia would be of interest to delay symptom worsening for individuals at higher risk of dementia.

For this work, we thus aimed to investigate the contribution of physical activity to cognitive reserve among consecutively enrolled MCI patients followed over up to 5 years from a large clinical cohort. In particular, we assessed the moderating effect of physical activity on the association between selected magnetic resonance imaging (MRI) and plasma biomarkers of brain pathology and conversion to dementia.

2 METHODS

2.1 Study population

The Memento cohort is a prospective clinic-based study aiming to better understand the natural history of AD and related disorders. Details of the study have been previously published.30 Briefly, 2323 participants consulting within 26 French memory clinics and presenting with either isolated cognitive complaints or recently diagnosed MCI were recruited from April 2011 to June 2014. Clinical MCI was defined as having a Clinical Dementia Rating (CDR) = 0.5. Participants were examined at baseline and followed every 6 to 12 months up to 5 years. Baseline data collection during face-to-face interview included socio-demographic characteristics, lifestyle factors, neurological and physical examination, and a full neuropsychological battery. Baseline brain MRI was mandatory for Memento participants but only 2183 had an MRI due to either post-consent refusal or contraindication. Of the 2183, 86% of participants included in the Memento cohort had a 3.0 Tesla MRI scan (1.5 Tesla for the others). Plasma samples were also obtained at baseline for all participants.

Among the 2323 Memento participants, 1194 participants were ≥ 60 years and had clinical MCI at baseline. We then excluded those without follow-up (n = 15), as well as participants with missing physical activity status at baseline (n = 135), leaving a final analytical sample of 1044 participants.

2.2 Physical activity definition

Physical activity data were collected using the short version of the International Physical Activity Questionnaire (IPAQ).31 It consists of seven questions self-assessing intensity of physical activity (vigorous, moderate, and walking) that people had been doing as part of their daily lives over the past 7 days. It estimates total physical activity in metabolic equivalent of task (MET)-minutes/week by multiplying the number of minutes dedicated to each activity class over a week by the specific MET score for that activity (walking = 3.3 METs, moderate = 4.0 METs, and vigorous = 8.0 METs). In addition, physical activity was also categorized as low, moderate, and high according to the IPAQ scoring protocol32: (1) high intensity was defined as engaging in either vigorous intensity activity on at least 3 days achieving a minimum total physical activity of at least 1500 MET minutes a week, or 7 or more days of any combination of walking, moderate intensity, or vigorous intensity activities achieving a minimum total physical activity of at least 3000 MET minutes a week; (2) moderate intensity was defined as engaging in either 3 or more days of vigorous intensity activity and/or walking of at least 30 minutes per day, or 5 or more days of moderate intensity activity and/or walking of at least 30 minutes per day, or 5 or more days of any combination of walking, moderate intensity, or vigorous intensity activities achieving a minimum total physical activity of at least 600 MET minutes a week; (3) participants who did not meet the above criteria were classified as having low level of physical activity.

RESEARCH IN CONTEXT

  1. Systematic Review: We searched PubMed for all articles investigating the interactions between physical activity and biomarkers of Alzheimer's disease and related dementias in relation to dementia risk or cognitive function or decline published up to October 1, 2022. Few studies investigated the moderating effect of physical activity on the associations between markers of brain pathology and dementia risk.

  2. Interpretation: In this prospective clinic-based cohort of participants with mild cognitive impairment (MCI), physical activity modified the association with dementia risk of both medial temporal lobe atrophy (MTA) and plasma amyloid beta (Aβ)42/40 ratio. Indeed, strengths of the associations between MTA and plasma Aβ42/40 ratio and dementia risk were attenuated for participants with higher levels of physical activity.

  3. Future Directions: Physical activity in late life may be an interesting modifiable target to reduce the negative impact of brain pathology on conversion from MCI to dementia.

2.3 Neuroimaging biomarkers of brain pathology

All neuroimaging acquisitions and analyses were coordinated by the Center for Acquisition and Treatment of Images (CATI; cati-neuroimaging.com), a platform dedicated to the management of multicenter neuroimaging studies.33 Scans were harmonized across centers, centralized, quality checked, and postprocessed to obtain standardized acquisitions. Medial temporal lobe atrophy (MTA) was rated visually by two trained physicians from the CATI team, using Scheltens’ scale.34 MTA was dichotomized according to validated cut-offs: high MTA was defined as a Scheltens’ scale score of 2 in either of the two hemispheres in individuals < 75 years, or a MTA score of 3 in individuals aged ≥ 75 years.35 White matter lesion (WML) severity was also rated by visual assessment of whole brain deep and periventricular lesions done centrally by two trained raters using the Fazekas scale.36, 37 A score of 0 to 3 was assigned separately to periventricular and subcortical WML (sum 0–6), and severe WML was defined as a Fazekas sum score of 4 to 6.

We investigated baseline measurement of MTA as a marker of hippocampal atrophy, a key structure in AD-related neurodegeneration, and WML as a marker of small vessel disease.

2.4 Plasma biomarkers of brain pathology

Plasma amyloid beta (Aβ)42, Aβ40, phosphorylated tau 181 (p-tau181) concentrations were measured using Simoa technology with commercial kits on a Quanterix HD-1 analyzer. Measures were performed in the same laboratory for all participants (Bordeaux University Hospital), blinded of clinical outcomes. Plasma Aβ42/40 ratio and p-tau181 were used as markers of amyloid and tau pathology, respectively.

2.5 Outcome definition

During a 5-year follow-up period, patients underwent a clinical and neurologic evaluation every 6 to 12 months. Incident cases of dementia were then assessed by trained neurologist according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision (DSM-IV) criteria. AD dementia was ascertained using criteria from the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). In addition, all dementia cases were reviewed and validated by an independent endpoint review committee composed of expert neurologists/geriatricians based on individuals’ case files.

2.6 Additional covariables

Education level was categorized as lower versus higher than high school level. Apolipoprotein E (APOE) ε4 status was defined as at least one ε4 allele carried versus none. Smoking status, as well as diabetes status and cardiovascular disease history, were self-reported at baseline. Hypertension was defined as either arterial pressure ≥ 140/90 mmHg or antihypertensive drug use. Body mass index (BMI) was objectively measured at baseline examination.

2.7 Statistical analysis

Participants’ characteristics at baseline were compared across physical activity levels using Kruskal–Wallis and χ2 tests, as appropriate. Associations between physical activity and each marker of brain pathology were tested using logistic regression for MTA and severe WML, and linear regression for plasma Aβ42/40 ratio and p-tau181 level, adjusted for age at baseline, sex, APOE ε4 status, education level, hypertension, and BMI.

To estimate dementia risks associated with physical activity, we performed Cox models with delay between study entry and event or censoring being the time scale. Participants who remained free of dementia were censored at the age of their last known dementia-free visit or at age of death. Aβ42/40 ratio was reverse coded so that higher levels represented greater amyloid pathology. Aβ42/40 ratio and p-tau181 were log-transformed and standardized. First, we evaluated the association between physical activity intensity (modeled either as log-transformed MET-minutes/week, or as categorical physical activity levels [low, moderate, and vigorous]) and dementia risk, without or with adjustments for the four different markers of brain pathologies. These models were additionally adjusted for age at baseline, sex, APOE ε4 status, education level, hypertension, and BMI.

Then, we generated dementia incidence rates according to levels of physical activity and of each marker of brain pathology using Poisson models adjusted for age at baseline, sex, APOE ε4 status, education level, hypertension, and BMI. For continuous plasmatic biomarkers, incidence rates are presented for both low and high (+/− 1 standard deviation [SD]) pathology (Aβ42/40 or p-tau181).

Moreover, interactions between physical activity levels and biomarkers of brain pathologies on dementia risks were added and tested within the initial Cox models (also adjusted for age at baseline, sex, APOE ε4 status, education level, hypertension, and BMI) to investigate the moderating effect of physical activity. Hazard ratios of the associations between each biomarker and dementia risk were presented for the three levels of physical activity. Similar models were performed with AD dementia as the outcome (non-AD dementia cases were censored at the end of the follow-up). In a post hoc analysis, we also tested whether the moderating effect of physical activity differed by biological sex.

Sensitivity analyses were performed to assess the robustness of our findings. The main results reported were based on a complete case analysis under the assumption that missing data for biomarkers and covariates (n = 134) were missing completely at random (MCAR). Multiple imputation by chained equations with a fully conditional specification (20 imputed data sets) was used to impute missing data to assess the plausibility of the MCAR assumption. Then, an alternative categorization for physical activity was used based on guidelines for physical activity, with a cut-off of at least 500 MET-minutes/week considered high physical activity. Finally, as plasma AD biomarker variability depend on kidney disease function,38 all models that included AD blood biomarkers either as exposure of interest or as potential confounder were adjusted for the glomerular filtration rate (using the Chronic Kidney Disease Epidemiology Collaboration definition).

Analyses were conducted using R (version 4.1.3).

3 RESULTS

Analytical sample characteristics are presented in Table 1. Participants were 72.7 years old on average, and more often women (59%). Half of the participants had a high education level, and 30% were APOE ε4 carriers. Compared to participants with low physical activity, those with moderate and high physical activity were more often APOE ε4 carriers, had higher education level, less often had hypertension, and had a lower BMI on average. Table S1 in supporting information shows associations between physical activity and biomarkers of brain pathologies. Globally, we found no differences according to physical activity, with only a trend toward less severe WML and higher levels of p-tau181 with higher levels of physical activity. Participants with missing biomarkers or covariates had higher levels of plasma amyloid pathology and less often severe WML (Table S2 in supporting information).

TABLE 1. Description of population characteristics according to physical activity levels, the Memento cohort.

Total

N = 1044

Low

N = 199

Moderate

N = 422

High

N = 423

P-value
Female 616 (59.0) 131 (65.8) 247 (58.5) 238 (56.3) 0.07
Age at baseline 72.7 (6.9) 73.1 (7.5) 73.0 (6.7) 72.1 (6.6) 0.09
APOE ε4 carriers 317 (30.4) 50 (26.3) 120 (30.0) 147 (36.7) 0.02
High education level 521 (49.9) 84 (42.2) 216 (51.2) 221 (52.2) 0.05
Smoker 74 (7.1) 17 (8.5) 31 (7.4) 26 (6.1) 0.53
Diabetes 129 (12.4) 32 (16.1) 45 (10.7) 52 (12.3) 0.16
Hypertension 657 (62.9) 139 (70.9) 271(65.5) 247 (59.5) 0.02
CVD history 164 (15.7) 32 (16.1) 77 (18.2) 55 (13.0) 0.11
BMI 25.6 (4.3) 26.8 (4.8) 25.6 (4.5) 25.0 (3.7) <0.01
MET-minute/week 2373 [1052–4568] 495 [244–884] 1646 [1074–2313] 5040 [3906–7383] <0.01
Aβ42/40 ratio 0.05 [0.05–0.06] 0.06 [0.05–0.06] 0.06 [0.05–0.06] 0.06 [0.05–0.06] 0.60
P-tau181 0.95 [0.60–1.45] 0.91 [0.57–1.38] 0.95 [0.60–1.45] 0.98 [0.64–1.50] 0.31
High MTA 208 (19.9) 35 (18.4) 76 (18.7) 97 (23.9) 0.13
Severe WML 292 (28.0) 58 (29.1) 126 (29.9) 108 (25.5) 0.34
  • Note: Categorical variable: N (%) ; Continuous variable: mean (sd) or median [IQR] as appropriate. (Missing data: APOE-ε4 = 53, Smoker = 1, Hypertension = 19, BMI = 13, Aβ4240 ratio = 28, P-tau181 = 17, MTA = 42).
  • Abbreviations: Aβ, amyloid beta; APOE, apolipoprotein E; BMI, body mass index; CVD, cardiovascular disease; MCI, mild cognitive impairment; MET, metabolic equivalent of task; MTA, medial temporal lobe atrophy; p-tau181, phosphorylated tau; WML, white matter lesions.

Over the 5-year follow-up, 202 dementia cases were diagnosed. Increasing physical activity (measured as continuous) was associated with lower risk of dementia, without (hazard ratio [HR] for 1 log MET-minute/week = 0.90 [95% confidence interval (CI): 0.82–0.98]) and with (HR = 0.83 [95% CI: 0.76–0.92]) adjustment for markers of brain pathologies (Table 2). Similarly, when studying physical activity as categorical exposure, compared to low physical activity, moderate and high physical activity tended to be associated with decreased dementia risk, although the association did not reach statistical significance (HR = 0.72 [95% CI: 0.49–1.06] and HR = 0.75 [95% CI: 0.51–1.10], respectively). After further adjustment for markers of brain pathologies, compared to low physical activity, the HRs for dementia declined and became statistically significant toward protective association (HR = 0.64 [95% CI: 0.44–0.94] for moderate physical activity and HR = 0.58 [95% CI: 0.39–0.86] for high physical activity). Strengths of the associations between moderate physical activity and risk of AD dementia were similar to the ones of dementia risk, while associations between high physical activity and AD dementia risk were weaker (Table 2).

TABLE 2. Associations between baseline physical activity and dementia (all and Alzheimer's disease) risks over 5-year follow-up.
All dementia Alzheimer's disease dementia
N = 910a HR (95% CI) P-value HR (95% CI) P-value
Model 1
Physical activity (per 1 log MET increase) 0.90 (0.82–0.98) 0.02 0.92 (0.83–1.02) 0.13
Physical activity
Moderate versus low 0.72 (0.49–1.06) 0.09 0.75 (0.49–1.16) 0.20
High versus low 0.75 (0.51–1.10) 0.14 0.85 (0.56–1.31) 0.46
Model 2
Physical activity (per 1 log MET increase) 0.83 (0.76–0.92) 0.0002 0.85 (0.7–0.95) 0.003
Physical activity
Moderate versus low 0.64 (0.44–0.94) 0.02 0.67 (0.43–1.03) 0.07
High versus low 0.58 (0.39–0.86) 0.007 0.66 (0.42–1.02) 0.06
  • Abbreviations: Aβ, amyloid beta; APOE, apolipoprotein E; BMI, body mass index; CI, confidence interval; HR, hazard ratio; MET, metabolic equivalent of task; MTA, medial temporal lobe atrophy; p-tau181, phosphorylated tau.
  • Note: Model 1: adjusted for age at baseline, sex, education level, APOE ε4 status, hypertension, and BMI. Model 2: Model 1 + additionally adjusted for markers of brain changes (medial temporal lobe atrophy, white matter lesions, and plasma levels of Aβ42/40 ratio and p-tau181).
  • a A total of 134 had missing data (APOE ε4 = 53, hypertension = 19, BMI = 13, Aβ4240 ratio = 28, p-tau181 = 17, MTA = 42).

Incidence rates of dementia per 1000 person-years according to physical activity level and to biomarkers of brain pathologies are displayed in Figure 1. We observe a trend for decreased incidence rates of dementia with increasing levels of physical activity, more marked in participants with higher levels of brain pathology. For high MTA and Aβ pathology, incidence rates of dementia were statistically significantly lower in people with high physical activity compared to those with low physical activity.

Details are in the caption following the image
Incidence rates of dementia per 1000 person-years according to physical activity and markers of cerebral lesion status. Aβ, amyloid beta; MTA, medial temporal lobe atrophy; WML, white matter lesions.

The study of the interactions between physical activity levels and biomarkers of brain pathologies on dementia risk are displayed in Table 3. In the group of participants with high level of physical activity, dementia risks associated with MTA and plasma Aβ42/40 ratio were statistically significantly weaker compared to the corresponding risks in the group of participants with low physical activity. As physical activity level increases, associations between MTA or amyloid pathology and dementia risk decreased. For instance, for an increase of 1 SD of Aβ42/40 ratio level (reverse coded; i.e., higher pathology levels), HRs for dementia were 1.64 (95% CI: 1.33–2.03) in persons with low physical activity compared to 1.23 (95% CI: 1.03–1.46) in persons with moderate physical activity and 1.09 (95% CI: 0.88–1.33) in persons with high physical activity. There were no statistically significant interactions between severe WML or plasma p-tau181 and physical activity on dementia risk. Regarding AD dementia, physical activity moderated the association between dementia risk and plasma Aβ42/40 (but not MTA). In addition, biological sex interacted with physical activity to moderate the associations between MTA or Aβ42/40 ratio and dementia risk, but not severe WML or p-tau181 level. MTA and Aβ42/40 ratio were more strongly associated with dementia risk in men compared to women. The moderating effect of physical activity on the association between MTA or Aβ42/40 ratio and dementia risk appeared to be stronger among men than women (Table S3 in supporting information).

TABLE 3. Associations between biomarkers of brain pathologies and risk of dementia stratified by levels of physical activity.
Low PA N = 178 HR (95% CI) Moderate PA N = 365 HR (95% CI) High PA N = 367 HR (95% CI) Moderate versus low P-value* High versus low P-value*
All dementia
Medial temporal lobe atrophy 4.48 (2.40–8.33) 2.90 (1.79–4.67) 1.85 (1.18–2.90) 0.28 0.02
Severe white matter lesions 1.01 (0.53–1.90) 1.26 (0.65–2.47) 0.71 (0.44–1.16) 0.56 0.39
Aβ42/40 ratio 1.64 (1.33–2.03) 1.23 (1.03–1.46) 1.09 (0.88–1.33) 0.04 0.007
P-tau181 1.33 (0.95–1.85) 1.64 (1.29–2.10) 1.46 (1.14–1.88) 0.31 0.64
Alzheimer's disease dementia
Medial temporal lobe atrophy 3.21 (1.54–6.71) 3.87 (2.29–6.54) 1.87 (1.15–3.04) 0.69 0.23
Severe white matter lesions 0.84 (0.40–1.76) 1.36 (0.80–2.30) 0.68 (0.40–1.15) 0.29 0.63
Aβ42/40 ratio 1.71 (1.35–2.17) 1.19 (0.97–1.46) 1.11 (0.89–1.46) 0.02 0.008
P-tau181 1.82 (1.23–2.69) 1.71 (1.30–2.26) 1.42 (1.08–1.86) 0.81 0.31
  • Abbreviations: Aβ, amyloid beta; APOE, apolipoprotein E; BMI, body mass index; CI, confidence interval; HR, hazard ratio; MET, metabolic equivalent of task; MRI, magnetic resonance imaging; PA, physical activity; MTA, medial temporal lobe atrophy; p-tau181, phosphorylated tau; SD, standard deviation; WML, white matter lesions.
  • Note: Models adjusted for age at baseline, sex, education level, APOE ε4 status, hypertension, BMI, and the three other markers of brain changes. MTA and WML are visually rated from MRI (Scheltens and Fazekas scales respectively), while Aβ42/40 ratio and p-tau181 levels are plasma measures. Plasma Aβ42/40 ratio was reverse coded so that higher levels represented greater amyloid pathology. Plasma Aβ42/40 ratio and p-tau181 were standardized and units correspond to 1 SD increase. HR for MTA and severe WML are presented for presence versus absence, while HR for plasma Aβ42/40 ratio and p-tau181 are presented for 1 SD increase.
  • *P-values of the interactions between physical activity and each biomarker.

Results from sensitivity analyses showed that our results were consistent both after imputing missing data under missing at random scenario and after adjusting for renal function (Table S4 in supporting information). When using a binary categorization of IPAQ (at least 500 MET-minutes/week: yes vs. no) based on physical activity recommendations, the moderating impact of higher physical activity on the association between MTA and dementia risk was attenuated whereas the moderating effect on other brain biomarkers was fairly consistent (Table S5 in supporting information).

4 DISCUSSION

In this prospective study of MCI patients, higher physical activity levels were associated with reduced risks of developing dementia when controlling for biomarkers of brain pathologies. In addition, physical activity moderated the relationship between biomarkers of both neurodegeneration and amyloid pathology and risk of dementia, leading to attenuated associations of both MTA and plasma Aβ42/40 ratio level with dementia risk for participants with the highest level of physical activity. We did not show evidence of a moderating effect of physical activity on the association between biomarkers of WML or tau pathologies on dementia risk. These results suggest that greater engagement in physical activity may contribute to cognitive reserve in specific ways and delay dementia onset in symptomatic older adults.

With the increasing prevalence of dementia, research focusing on modifiable factors promoting resilience, even for individuals at higher risk, is necessary to attempt to reduce the global burden related to dementia. Our findings are somewhat consistent with the rich literature suggesting a protective effect of physical activity on dementia risk.5, 39 These results also add knowledge on the impact of physical activity on the conversion from MCI to dementia.9, 40, 41 They also complement evidence showing better cognitive and functional outcomes following exercise interventions among dementia patients.42, 43 Yet, we did not evidence relationships between physical activity and brain pathologies consistent across the markers investigated. These results do not support the hypothesis that physical activity reduces dementia risk by preventing or delaying brain changes related to dementia development. This hypothesis would still need to be tested further in a setting in which the associations between physical activity and brain pathologies can be studied longitudinally.

Neuropathological and neuroimaging studies have suggested that many people may tolerate considerable cerebral changes without expressing clinical symptoms, consistent with the cognitive reserve concept.20 Our results support this body of literature, as participants with higher physical activity experienced lower dementia risk while presenting with similar levels of brain pathologies. Cognitive reserve can be influenced by the interaction of innate individual differences and lifetime exposures such as lifestyle factors. The biological mechanisms underlying cognitive reserve lie in the adaptability of functional brain processes. Physical activity, by contributing to cognitive reserve, may allow physically active individuals with MCI to compensate, through increased synaptogenesis, for the negative effect of amyloid pathology and atrophy in the brain, thus tolerating more damage before developing cognitive impairment.19 Late-life physical activity may also enhance efficiency, capacity, or flexibility of brain networks when performing cognitive functions.44

To appropriately investigate cognitive reserve mechanisms, a cognitive reserve–related factor, a brain measure, and a cognitive measure are required.21 Up to date, only a few studies have explored the contribution of physical activity to cognitive reserve while accounting for brain pathology.22, 24-26, 28, 29, 45 They yielded heterogeneous findings. Our work evidenced weaker associations of MTA and plasma Aβ42/40 ratio level with dementia risk across increasing levels of physical activity. Two studies from the Chicago Health and Aging Project showed a non-significant trend toward slower cognitive decline with higher physical activity, even for participants with high levels of serum neurofilament light chain and total tau.25, 26 Another study reported that greater engagement in physical activity was protective against Aβ-related cognitive decline and neurodegeneration in 182 asymptomatic older adults.24 In addition, from the Rush Memory and Aging Project study that used objectively measured physical activity, it was reported that within-person increase in physical activity attenuated the association between AD pathology and cognition.27 Unlike our results, two other studies reported a moderating effect of physical activity on the associations of white matter hyperintensities with cognition.22, 46 Memel et al. also reported that baseline physical activity attenuated the association between cerebrovascular pathology and cognition.27 The absence of an interaction between physical activity and severe WML in our work may be due to characteristics of our study sample, as severe WML were not significantly associated with higher dementia risk in our study. However, two studies did not show an association between physical activity and markers of cognitive reserve using a residual approach for cognitive reserve.28, 29 In addition, although physical activity was associated with better cognition after controlling for different brain pathologies, Buchman et al. did not evidence that a more active lifestyle modified the associations of brain pathologies with cognitive function proximate to death.45 Only a few studies investigated the moderating effect of physical activity on tau pathology with dementia risk or cognition. The absence of interaction we found may be due to the fact that individuals with high tau pathology may be too advanced in the disease process to benefit from physical activity's effects. In addition, only a few studies have looked at tau pathology and cognitive reserve;47, 48 thus, future studies are needed to validate our results. Taken together, our results and others’ support the hypothesis that different lifestyle factors may only moderate specific, but not all, markers of brain pathologies on cognition.

In addition to the type of pathology, both physical activity measurement and population characteristics may contribute to differences in results. Most studies investigating the contribution of physical activity to cognitive reserve used self-reported physical activity measures assessed through standardized questionnaires, which may be unreliable. However, questionnaires allow us to collect information on physical activity intensity and frequency. In our work, moderate physical activity was associated with a lower risk of dementia after adjustment for brain pathologies, but it was not significantly moderating the association between MTA and dementia risk. It seems that only higher levels of physical activity are required to significantly mitigate the negative association between brain atrophy and dementia risk. A few studies also used objective measures through pedometers or accelerometers, yet assessed physical activity over a limited period of time.24, 27, 45 Finally, regarding population characteristics, most studies were realized among population-based clinically normal older adults. This work thus extends previous findings to persons with MCI who are at risk of developing dementia. Moreover, our results suggest that physical activity may contribute to cognitive reserve more strongly in men than in women, potentially due to stronger associations between biomarkers of brain pathologies and dementia risk among men in the Memento cohort. Additional studies are required to confirm these sex differences.

This study has some limitations. First, physical activity exposure was self-reported at baseline, thus misclassification may have occurred and could have conferred to biased results. Moreover, low engagement in physical activity may be due to reverse causation, that is, people may become less physically active during the years preceding dementia onset, and biomarkers of brain pathologies were only measured once at baseline, thus causal interpretations must be drawn with caution. In addition, our physical activity questionnaire allowed us to assess physical activity within the past 7 days. Although this issue is common in studies assessing physical activity, it may not be representative of long-term physical activity habits. Participants excluded due to missingness had higher plasma amyloid levels and less severe WML; thus, our results may be specific to our study population. The sensitivity analysis using multiple imputation to account for selection yielded similar results, suggesting that the characteristics of the excluded participants in this study did not influence the moderation results. Finally, we used plasmatic markers of AD-related cerebral lesions, which may be less reliable than positron emission tomography or cerebrospinal fluid amyloid/tau markers. Still, plasmatic markers have been shown to associate with AD-related pathology and dementia risk49 and our sensitivity analysis accounting for renal function yielded consistent results. In addition, the Simoa platform was used for plasma AD biomarker quantification. It would be interesting to further assess the robustness of our results using alternative quantification of plasma AD biomarkers such as mass spectrometry-based methods that have been suggested to be stronger predictors of amyloid positivity.50 It should also be noted that plasma biomarkers were not measured in duplicate. Nevertheless, several controls of reproducibility were realized on subsets throughout the study, leading to very satisfactory results.

This study also has important strengths and contributes to our understanding of the influence of physical activity with dementia risk. The Memento study provides an adequate setting to investigate, within a large sample size, the contribution of physical activity to cognitive reserve, due to the large availability of various neuroimaging and plasmatic AD-related markers. Additionally, this work relies on well-defined dementia cases, as each case was reviewed by a validation committee. Although self-reported, physical activity was assessed by a standardized and validated questionnaire, allowing us to investigate different levels of activity.

In conclusion, this work suggests that, in persons with MCI, higher levels of physical activity may attenuate the impact of cerebral atrophy and amyloid pathology on the risk of developing dementia. These results suggest potential pathways for modifying the effect of amyloid pathology and cerebral atrophy on cognition and dementia. They also suggest that promoting engagement in physical activity in persons at risk of developing dementia could delay dementia onset. Future studies adding longitudinal measures of markers of brain pathologies are needed to confirm the mechanisms involved in the association between physical activity and dementia.

ACKNOWLEDGMENTS

The MEMENTO cohort is funded by the Foundation Plan Alzheimer (Alzheimer Plan 2008-2012), through the Plan Maladies Neurodégénératives (2014-2019), and the French Ministry of Research (MESRI, DGRI 2020-2024). This work was also supported by CIC 1401-EC, Bordeaux University Hospital (CHU Bordeaux, sponsor of the cohort), Inserm, and the University of Bordeaux. The MEMENTO cohort has received funding support from AVID, GE Healthcare, and FUJIREBIO through private–public partnerships. Sponsors and funders were not involved in the study conduct, analysis, or interpretation of data nor in the writing of the manuscript.

    CONFLICT OF INTEREST STATEMENT

    The authors have nothing to report. Author disclosures are available in the supporting information.

    CONSENT STATEMENT

    All participants provided written informed consent.

    APPENDIX

    1 MEMENTO COHORT STUDY GROUP COLLABORATORS

    Name Degree Location Role
    Michèle Allard MD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Xavier Arnozan, F-33000, Bordeaux, France Co-investigator
    Sandrine Andrieu MD, PhD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Pierre Anthony MD, PhD Memory Resource and Research Centre of Colmar, Hôpitaux Civils de Colmar, F-68000, Colmar, France Co-investigator
    Christine Astier MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Alexandre Augier MD, PhD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Nicolas Auguste MD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital de la Charité, F-42000, Saint-Etienne, France Co-investigator
    Sophie Auriacombe MD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, F-33000, Bordeaux, France Co-investigator
    John Avet MD, PhD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital Nord, F-42000, Saint-Etienne, France Co-investigator
    Olivier Bailon MD, PhD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Fabrice-Guy Barral MD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital Nord, F-42000, Saint-Etienne, France Co-investigator
    Jean Barré MD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Annick Barthelaix MD, PhD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Catherine Bayle MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Olivier Beauchet Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Catherine Belin MD, PhD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Samia Belkacem MD Institute of Memory and Alzheimer's Disease (IM2A), Centre for NeuroImaging Research (CENIR), Brain and Spine Institute (ICM), UMR S 1127, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris, France Co-investigator
    Douraied Ben Salem MD, PhD Memory Resource and Research Centre of Brest, CHRU de Brest, F-29000, Brest, France Co-investigator
    Karim Bennys MD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Hôpital Gui de Chauliac, F-34000, Montpellier, France Co-investigator
    Géraldine Bera MD Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, Inserm U1146, CNRS UMR 7371, France NeuroSpin, I2BM, Commissariat à l'Energie Atomique, Paris, France Co-investigator
    Eric Berger MD Memory Resource and Research Centre of Besançon, CHU de Besançon, Hôpital Jean Minjoz, Hôpital Saint-Jacques, F-25000, Besançon, France Co-investigator
    Marc G. Berger MD, PhD Memory Resource and Research Centre of Clermont-Ferrand, CHU de Clermont-Ferrand, F-63000, Clermont-Ferrand, France Co-investigator
    Emilie Bergouin MD Memory Resource and Research Centre of Dijon, CHU Dijon Bourgogne, Hôpital du Bocage, Hôpital de Champmaillot, F-21000, Dijon, France Co-investigator
    François Bertin-Hugault MD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Guillaume Bertrand MD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    François-Xavier Bertrand MD, PhD Memory Resource and Research Centre of Nantes, CHU de Nantes, F-44000, Nantes, France Co-investigator
    Catherine Beze MD Memory Resource and Research Centre of Center Region, CHRU de Tours, Hôpital Bretonneau, F-37000, Tours, France Co-investigator
    Valérie Boilet Coordinating Centre, Inserm CIC-1401 Clinical Epidemiology, CHU de Bordeaux, F-33000, Bordeaux, France Co-investigator
    Stéphanie Bombois MD, PhD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Alain Bonafé MD, PhD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Montpellier, France Co-investigator
    Yasmina Boudali MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Hatem Bouhladour MD, PhD Memory Resource and Research Centre of Besançon, CHU de Besançon, Hôpital Jean Minjoz, Hôpital Saint-Jacques, F-25000, Besançon, France Co-investigator
    Clémence Boully MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Isabelle Bourdel-Marchasson MD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Xavier Arnozan, F-33000, Bordeaux, France Co-investigator
    Vincent Bouteloup PharmD Coordinating Centre, Inserm CIC-1401 Clinical Epidemiology, CHU de Bordeaux, F-33000, Bordeaux, France Co-investigator
    Claire Boutet MD Institute of Memory and Alzheimer's Disease (IM2A), Centre for NeuroImaging Research (CENIR), Brain and Spine Institute (ICM), UMR S 1127, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris, France Co-investigator
    Serge Bracard MD, PhD Memory Resource and Research Centre of Nancy, CHU de Nancy, F-54000, Nancy, France Co-investigator
    Antoine Brangier MD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Pierre-Yves Brillet MD, PhD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Laure Caillard MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Fabienne Calvas MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital Purpan, F-31000, Toulouse, France Co-investigator
    Agnès Camus MD Memory Resource and Research Centre of Dijon, CHU Dijon Bourgogne, Hôpital du Bocage, Hôpital de Champmaillot, F-21000, Dijon, France Co-investigator
    Vincent Camus MD, PhD Memory Resource and Research Centre of Center Region, CHRU de Tours, Hôpital Bretonneau, F-37000, Tours, France Co-investigator
    Sandrine Canaple MD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Antoine Carpentier MD, PhD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Pascaline Cassagnaud MD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Françoise Cattin MD Memory Resource and Research Centre of Besançon, CHU de Besançon, Hôpital Jean Minjoz, Hôpital Saint-Jacques, F-25000, Besançon, France Co-investigator
    Ludivine Chamard MD Memory Resource and Research Centre of Besançon, CHU de Besançon, Hôpital Jean Minjoz, Hôpital Saint-Jacques, F-25000, Besançon, France Co-investigator
    Stéphane Chanalet MD Memory Resource and Research Centre of Nice, CHU de Nice, Hôpital Pasteur, F-06100, Nice, France Co-investigator
    Mathieu Chastan MD Memory Resource and Research Centre of Rouen, CLCC Henri Becquerel, Rouen, France Co-investigator
    Sophie Chauvelier MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Valérie Chauvire MD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Samia Cheriet MD, PhD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital Purpan, F-31000, Toulouse, France Co-investigator
    Anthony Clotagatide MD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital Nord, F-42000, Saint-Etienne, France Co-investigator
    Emmanuel Cognat MD, PhD Memory Resource and Research Centre of Paris Nord, AP-HP, Paris, France Co-investigator
    Lora Cohen PhD Memory Resource and Research Centre of Grenoble, CHU de Grenoble Alpes, Grenoble, France Co-investigator
    Jean-Marc Constans MD, PhD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Marie-Hélène Coste MD, PhD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Jean-Philippe Cottier MD, PhD Memory Resource and Research Centre of Center Region, CHRU de Tours, Hôpital Bretonneau, F-37000, Tours, France Co-investigator
    François Cotton MD, PhD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Isabelle Couret MD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Hôpital Gui de Chauliac, F-34000, Montpellier, France Co-investigator
    Olivier-François Couturier MD, PhD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Pascale Cowppli-Bony MD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, F-33000, Bordeaux, France Co-investigator
    Véronique Cressot MD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Xavier Arnozan, F-33000, Bordeaux, France Co-investigator
    Benjamin Crétin MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Keren Danaila MD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Jacques Darcourt MD, PhD Memory Resource and Research Centre of Nice, CLCC Antoine Lacassagne, Nice, France Co-investigator
    Jean-François Dartigues MD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, F-33000, Bordeaux, France Co-investigator
    Ana-Maria Dascalita MD, PhD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital de la Charité, F-42000, Saint-Etienne, France Co-investigator
    Renaud David MD, PhD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Xavier De Petigny MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Delphine De Verbizier-Lonjon MD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Hôpital Gui de Chauliac, F-34000, Montpellier, France Co-investigator
    Marielle Decousus MD, PhD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital Nord, F-42000, Saint-Etienne, France Co-investigator
    Isabelle Defouilloy MD, PhD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Christine Delmaire MD, PhD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Julien Delrieu MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Catherine Demuyinck MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Vincent Deramecourt MD, PhD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Hervé Deramond MD, PhD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Thomas Desmidt MD, PhD Memory Resource and Research Centre of Center Region, CHRU de Tours, Hôpital Bretonneau, F-37000, Tours, France Co-investigator
    Marie-Dominique Desruet PharmD, PhD Memory Resource and Research Centre of Grenoble, CHU de Grenoble Alpes, Grenoble, France Co-investigator
    Julien Detour Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Agnès Devendeville MD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Mira Didic MD, PhD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Maritchu Doireau MD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, F-33000, Bordeaux, France Co-investigator
    Antonio Dos Santos MD Institute of Memory and Alzheimer's Disease (IM2A), Brain and Spine Institute (ICM), UMR S 1127, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris, France Co-investigator
    Patrice Douillet MD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Hôpital Gui de Chauliac, F-34000, Montpellier, France Co-investigator
    Foucaud Du Boisgueheneuc MD Memory Resource and Research Centre of Poitiers, CHU de Poitiers, Hôpital de La Milétrie, F-86000, Poitiers, France Co-investigator
    Delphine Dubail MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Laure Ducroq-Ducastaing MD Memory Resource and Research Centre of Brest, CHRU de Brest, F-29000, Brest, France Co-investigator
    Julien Dumurgier MD, PhD Memory Resource and Research Centre of Paris Nord, AP-HP, Paris, France Co-investigator
    Diane Dupuy MD, PhD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Emmanuelle Duron MD, PhD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Inna Dygai-Cochet MD, PhD Memory Resource and Research Centre of Dijon, CLCC Georges François Leclerc, Dijon, France Co-investigator
    Véronique Eder MD, PhD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Stéphane Epelbaum MD, PhD Institute of Memory and Alzheimer's Disease (IM2A), Brain and Spine Institute (ICM), UMR S 1127, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris, France Co-investigator
    Frédérique Etcharry-Bouyx MD, PhD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Daniel Fagret MD, PhD Memory Resource and Research Centre of Grenoble, CHU de Grenoble Alpes, Grenoble, France Co-investigator
    Catherine Faisant MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Karim Farid MD, PhD Memory Resource and Research Centre of Paris Nord, AP-HP, Paris, France Co-investigator
    Denis Fédérico MD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Olivier Felician MD, PhD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Philippe Fernandez MD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, F-33000, Bordeaux, France Co-investigator
    Pacôme Fosse MD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Alexandra Foubert-Samier MD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, F-33000, Bordeaux, France Co-investigator
    Isabelle Franck MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Monique Galitzky MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital Purpan, F-31000, Toulouse, France Co-investigator
    Céline Gallazzini-Crepin MD Memory Resource and Research Centre of Grenoble, CHU de Grenoble Alpes, Grenoble, France Co-investigator
    Radka Gantchev MD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Laurence Garbarg-Chenon MD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Guillaume Gautier MD, PhD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Emmanuel Gerardin MD, PhD Memory Resource and Research Centre of Rouen, Neuroradiology Department, Rouen University Hospital, F-76031, Rouen, France Co-investigator
    Claire Gervais MD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Jean-Claude Getenet MD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital Nord, F-42000, Saint-Etienne, France Co-investigator
    Nadine Girard MD, PhD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Fabienne Giraud MD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Chantal Girtanner MD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital de la Charité, F-42000, Saint-Etienne, France Co-investigator
    Valérie Gissot MD Memory Resource and Research Centre of Center Region, CHRU de Tours, Hôpital Bretonneau, F-37000, Tours, France Co-investigator
    Caroline Grangeon PharmD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Daniel Grucker MD, PhD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Eric Guedj MD, PhD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Claude Gueriot MD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Yves Guilhermet MD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Rémy Guillevin MD, PhD Memory Resource and Research Centre of Poitiers, CHU de Poitiers, Hôpital de La Milétrie, F-86000, Poitiers, France Co-investigator
    Sophie Haffen MD Memory Resource and Research Centre of Besançon, CHU de Besançon, Hôpital Jean Minjoz, Hôpital Saint-Jacques, F-25000, Besançon, France Co-investigator
    Didier Hannequin MD, PhD Memory Resource and Research Centre of Rouen, Neurology Department, Rouen University Hospital, F-76031, Rouen, France Co-investigator
    Sandrine Harston MD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Xavier Arnozan, F-33000, Bordeaux, France Co-investigator
    Anne Hitzel MD, PhD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital Purpan, F-31000, Toulouse, France Co-investigator
    Caroline Hommet MD, PhD Memory Resource and Research Centre of Center Region, CHRU de Tours, Hôpital Bretonneau, F-37000, Tours, France Co-investigator
    Claude Hossein-Foucher MD, PhD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Fabrice Hubele MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Agnès Jacquin-Piques MD, PhD Memory Resource and Research Centre of Dijon, CHU Dijon Bourgogne, Hôpital du Bocage, Hôpital de Champmaillot, F-21000, Dijon, France Co-investigator
    Betty Jean MD Memory Resource and Research Centre of Clermont-Ferrand, CHU de Clermont-Ferrand, F-63000, Clermont-Ferrand, France Co-investigator
    Joanne Jenn MD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Xavier Arnozan, F-33000, Bordeaux, France Co-investigator
    Laure Joly MD, PhD Memory Resource and Research Centre of Nancy, CHU de Nancy, F-54000, Nancy, France Co-investigator
    Thérèse Jonveaux MD Memory Resource and Research Centre of Nancy, CHU de Nancy, F-54000, Nancy, France Co-investigator
    Adrien Julian MD, PhD Memory Resource and Research Centre of Poitiers, CHU de Poitiers, Hôpital de La Milétrie, F-86000, Poitiers, France Co-investigator
    Aurélie Kas MD, PhD Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, Inserm U1146, CNRS UMR 7371, France NeuroSpin, I2BM, Commissariat à l'Energie Atomique, Paris, France Co-investigator
    Anna Kearney-Schwartz MD Memory Resource and Research Centre of Nancy, CHU de Nancy, F-54000, Nancy, France Co-investigator
    Alice Keles MD Memory Resource and Research Centre of Nancy, CHU de Nancy, F-54000, Nancy, France Co-investigator
    Antony Kelly MD Memory Resource and Research Centre of Clermont-Ferrand, Centre de Lutte contre le Cancer, F-63000, Clermont-Ferrand, France Co-investigator
    Nathalie Keromnes MD Memory Resource and Research Centre of Brest, CHRU de Brest, F-29000, Brest, France Co-investigator
    Lejla Koric MD Memory Resource and Research Centre of Marseille, CHU de Marseille, Hôpital La Timone, F-13000, Marseille, France Co-investigator
    Alexandre Krainik MD, PhD Memory Resource and Research Centre of Grenoble, CHU de Grenoble Alpes, Grenoble, France Co-investigator
    Stéphane Kremer MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Florian Labourée MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Franck Lacoeuille MD, PhD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Francoise Lala MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Chantal Lamy MD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Jean-Louis Laplanche PharmD, PhD Memory Resource and Research Centre of Paris Nord, AP-HP, Paris, France Co-investigator
    Cyrille Launay MD, PhD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Stéphane Lehericy MD, PhD Institute of Memory and Alzheimer's Disease (IM2A), Centre for NeuroImaging Research (CENIR), Brain and Spine Institute (ICM), UMR S 1127, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris, France Co-investigator
    Sylvain Lehmann MD, PhD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Hôpital Gui de Chauliac, F-34000, Montpellier, France Co-investigator
    Hermine Lenoir MD, PhD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Marcel Levy MD, PhD Institute of Memory and Alzheimer's Disease (IM2A), Brain and Spine Institute (ICM), UMR S 1127, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris, France Co-investigator
    Stéphanie Libercier MD, PhD Memory Resource and Research Centre of Colmar, Hôpitaux Civils de Colmar, F-68000, Colmar, France Co-investigator
    Marie-Anne Mackowiak-Cordoliani MD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Eloi Magnin MD Memory Resource and Research Centre of Besançon, CHU de Besançon, Hôpital Jean Minjoz, Hôpital Saint-Jacques, F-25000, Besançon, France Co-investigator
    Zaza Makaroff MD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Athina Marantidou MD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Isabelle Marcet MD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, F-33000, Bordeaux, France Co-investigator
    Cécilia Marelli MD, PhD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Hôpital Gui de Chauliac, F-34000, Montpellier, France Co-investigator
    Sophie Marilier MD Memory Resource and Research Centre of Dijon, CHU Dijon Bourgogne, Hôpital du Bocage, Hôpital de Champmaillot, F-21000, Dijon, France Co-investigator
    Idalie Martin MD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Olivier Martinaud MD, PhD Memory Resource and Research Centre of Rouen, Neurology Department, Rouen University Hospital, F-76031, Rouen, France Co-investigator
    Catherine Martin-Hunyadi MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Aïcha Medjoul MD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Isabelle Merlet MD Memory Resource and Research Centre of Poitiers, CHU de Poitiers, Hôpital de La Milétrie, F-86000, Poitiers, France Co-investigator
    Danielle Mestas MD Memory Resource and Research Centre of Clermont-Ferrand, CHU de Clermont-Ferrand, F-63000, Clermont-Ferrand, France Co-investigator
    Marc-Etienne Meyer MD, PhD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Jean-Marc Michel MD Memory Resource and Research Centre of Colmar, Hôpitaux Civils de Colmar, F-68000, Colmar, France Co-investigator
    Agnès Michon MD Institute of Memory and Alzheimer's Disease (IM2A), Brain and Spine Institute (ICM), UMR S 1127, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris, France Co-investigator
    Isabelle Migeon-Duballet MD Memory Resource and Research Centre of Poitiers, CHU de Poitiers, Hôpital de La Milétrie, F-86000, Poitiers, France Co-investigator
    Karl Mondon MD, PhD Memory Resource and Research Centre of Center Region, CHRU de Tours, Hôpital Bretonneau, F-37000, Tours, France Co-investigator
    Clément Morgat PharmD, PhD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Pellegrin, F-33000, Bordeaux, France Co-investigator
    Véronique Moullart MD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Christian Moussard MD Memory Resource and Research Centre of Besançon, CHU de Besançon, Hôpital Jean Minjoz, Hôpital Saint-Jacques, F-25000, Besançon, France Co-investigator
    Aurélie Mouton MD, PhD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Izzie Jacques Namer MD, PhD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Georges Niewiadomski MD, PhD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Guillaume Nivaggioni MD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Marie Noblet MD, PhD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Michel Nonent MD, PhD Memory Resource and Research Centre of Brest, CHRU de Brest, F-29000, Brest, France Co-investigator
    Fati Nourhashemi MD, PhD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Hélène Oesterle MD Memory Resource and Research Centre of Colmar, Hôpitaux Civils de Colmar, F-68000, Colmar, France Co-investigator
    Galdric Orvoen MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Pierre Jean Ousset MD, PhD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Amandine Pallardy MD Memory Resource and Research Centre of Nantes, CHU de Nantes, F-44000, Nantes, France Co-investigator
    Claire Paquet MD, PhD Memory Resource and Research Centre of Paris Nord, AP-HP, Paris, France Co-investigator
    Pierre-Yves Pare MD, PhD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Anne Pasco MD, PhD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Pierre Payoux MD, PhD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital Purpan, F-31000, Toulouse, France Co-investigator
    Cécile Pays MD, PhD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Hôpital Gui de Chauliac, F-34000, Montpellier, France Co-investigator
    Isabelle Pellegrin MD, PhD Biological Research Centre, CHU de Bordeaux, F-33000, Bordeaux, France Co-investigator
    Rémy Perdrisot MD, PhD Memory Resource and Research Centre of Poitiers, CHU de Poitiers, Hôpital de La Milétrie, F-86000, Poitiers, France Co-investigator
    Bertille Perin MD, PhD Memory Resource and Research of Amiens, CHU Amiens Picardie, F-80000, Amiens, France Co-investigator
    Christine Perret-Guillaume MD, PhD Memory Resource and Research Centre of Nancy, CHU de Nancy, F-54000, Nancy, France Co-investigator
    Grégory Petyt MD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Nathalie Philippi MD, PhD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Geneviève Pinganaud MD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Xavier Arnozan, F-33000, Bordeaux, France Co-investigator
    Matthieu Plichart MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Gabriel Pop MD, PhD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Michèle Puel MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital Purpan, F-31000, Toulouse, France Co-investigator
    Mathieu Queneau MD, PhD Memory Resource and Research Centre of Paris Nord, Centre Cardiologique du Nord, Paris, France Co-investigator
    Solène Querellou MD Memory Resource and Research Centre of Brest, CHRU de Brest, F-29000, Brest, France Co-investigator
    Muriel Quillard-Muraine MD, PhD Memory Resource and Research Centre of Rouen, Neurology Department, Rouen University Hospital, F-76031, Rouen, France Co-investigator
    Valérie Quipourt MD, PhD Memory Resource and Research Centre of Dijon, CHU Dijon Bourgogne, Hôpital du Bocage, Hôpital de Champmaillot, F-21000, Dijon, France Co-investigator
    Chloé Rachez MD, PhD Memory Resource and Research Centre of Clermont-Ferrand, CHU de Clermont-Ferrand, F-63000, Clermont-Ferrand, France Co-investigator
    Micheline Razzouk-Cadet MD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Anne-Sophie Rigaud MD, PhD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Hélène Robin-Ismer MD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Mathieu Rodallec MD, PhD Memory Resource and Research Centre of Paris Nord, Centre Cardiologique du Nord, Paris, France Co-investigator
    Yves Rolland MD, PhD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Adeline Rollin-Sillaire MD, PhD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Olivier Rouaud MD Memory Resource and Research Centre of Dijon, CHU Dijon Bourgogne, Hôpital du Bocage, Hôpital de Champmaillot, F-21000, Dijon, France Co-investigator
    Caroline Roubaud MD, PhD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Isabelle Rouch MD, PhD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Julie Roux MD, PhD Memory Resource and Research Centre of Grenoble, CHU de Grenoble Alpes, Grenoble, France Co-investigator
    Guillaume Sacco MD, PhD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Pierre-Yves Salaun MD Memory Resource and Research Centre of Brest, CHRU de Brest, F-29000, Brest, France Co-investigator
    François Salmon MD, PhD Memory Resource and Research Centre of Poitiers, CHU de Poitiers, Hôpital de La Milétrie, F-86000, Poitiers, France Co-investigator
    Alicia Sanchez MD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital Nord, F-42000, Saint-Etienne, France Co-investigator
    Maria-Joao Santiago-Ribeiro MD, PhD Memory Resource and Research Centre of Center Region, CHRU de Tours, Hôpital Bretonneau, F-37000, Tours, France Co-investigator
    Alain Sarciron MD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Nathalie Sastre-Hengan MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Mathilde Sauvée MD, PhD Memory Resource and Research Centre of Grenoble, CHU de Grenoble Alpes, Grenoble, France Co-investigator
    Christian Scheiber MD, PhD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Anne-Marie Schneider MD, PhD Memory Resource and Research Centre of Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000, Strasbourg, France Co-investigator
    Franck Semah MD, PhD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Amélie Serra MD Memory Resource and Research Centre of Grenoble, CHU de Grenoble Alpes, Grenoble, France Co-investigator
    Marie-Laure Seux MD Memory Resource and Research Centre of Paris Broca, AP-HP, Paris, France Co-investigator
    Hélène Sordet-Guépet MD Memory Resource and Research Centre of Dijon, CHU Dijon Bourgogne, Hôpital du Bocage, Hôpital de Champmaillot, F-21000, Dijon, France Co-investigator
    Maria Eugenia Soto MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Mathieu Tafani MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital Purpan, F-31000, Toulouse, France Co-investigator
    Jean-Yves Tanguy MD, PhD Memory Resource and Research Centre of Angers, CHU d'Angers, F-49000, Angers Co-investigator
    Michael Taroux MD, PhD Memory Resource and Research Centre of Dijon, CHU Dijon Bourgogne, Hôpital du Bocage, Hôpital de Champmaillot, F-21000, Dijon, France Co-investigator
    Marc Teichmann MD, PhD Institute of Memory and Alzheimer's Disease (IM2A), Brain and Spine Institute (ICM), UMR S 1127, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris, France Co-investigator
    Catherine Terrat MD, PhD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital de la Charité, F-42000, Saint-Etienne, France Co-investigator
    Jamila Thabet MD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Claire Thalamas MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital Purpan, F-31000, Toulouse, France Co-investigator
    Catherine Thomas-Anterion MD, PhD Memory Resource and Research Centre of Saint-Etienne, CHU de Saint-Etienne, Hôpital Nord, F-42000, Saint-Etienne, France Co-investigator
    Anne-Cécile Troussière MD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Renata Ursu MD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator
    Pierre Vera MD, PhD Memory Resource and Research Centre of Rouen, CLCC Henri Becquerel, Rouen, France Co-investigator
    Martine Vercelletto MD Memory Resource and Research Centre of Nantes, CHU de Nantes, F-44000, Nantes, France Co-investigator
    Olivier Vercruysse MD Memory Resource and Research Centre of Lille, CHRU de Lille, Hôpital Roger Salengro, F-59000, Lille, France Co-investigator
    Antoine Verger MD, PhD Memory Resource and Research Centre of Nancy, CHU de Nancy, F-54000, Nancy, France Co-investigator
    Philippe Viau MD Memory Resource and Research Centre of Nice, CHU de Nice, Institut Claude Pompidou, F-06100, Nice, France Co-investigator
    Marie-Neige Videau MD Memory Resource and Research Centre of Bordeaux, CHU de Bordeaux, Hôpital Xavier Arnozan, F-33000, Bordeaux, France Co-investigator
    Thierry Voisin MD Memory Resource and Research Centre of Toulouse, CHU de Toulouse, Hôpital La Grave-Casselardit, F-31000, Toulouse, France Co-investigator
    Nathalie Wagemann MD, PhD Memory Resource and Research Centre of Nantes, CHU de Nantes, F-44000, Nantes, France Co-investigator
    Aziza Waissi-Sediq MD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Jing Xie MD, PhD Memory Resource and Research Centre of Lyon, Hospices Civils de Lyon, Hôpital des Charpennes, F-69000, Lyon, France Co-investigator
    Nathanaëlle Yeni MD Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, Inserm U1146, CNRS UMR 7371, France NeuroSpin, I2BM, Commissariat à l'Energie Atomique, Paris, France Co-investigator
    Michel Zanca MD, PhD Memory Resource and Research Centre of Montpellier, CHU de Montpellier, Hôpital Gui de Chauliac, F-34000, Montpellier, France Co-investigator
    Jean Zinszner MD, PhD Memory Clinic, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris-Seine-Saint-Denis, F-93009, Bobigny, France Co-investigator