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Diabetes Mellitus and Cognition: Pathway Analysis in the MEMENTO Cohort
Eric Frison1, Cecile Proust-Lima1, Jean-Francois Mangin1
1From INSERM, UMR 1219 (E.F., C.P.-L., G.C., C.D.), and INSERM, CIC1401-EC (E.F., G.C., C.D.), Université de Bordeaux; Pole de Sante Publique Centre (E.F., G.C., C.D.) and Pole de Gérontologie Clinique (I.B.-M.), Hospitalier Universitaire (CHU) de Bordeaux; CATI Multicenter Neuroimaging Platform (J.-F.M., M.-O.H., M. Ceccaldi), Paris; Neurospin CEA Paris Saclay University (J.-F.M.), Gif-sur-Yvette; Laboratoire d'Imagerie Biomédicale (M.-O.H.), INSERM, CNRS, Sorbonne Université; Médecine Nucléaire (M.-O.H.), AP-HP, Hôpital Pitié-Salpêtrière; IM2A, AP-HP, INSERM, UMR-S975, Groupe Hospitalier, Pitié-Salpêtrière Institut de la Mémoire et de la Maladie d'Alzheimer (S.B.), and INSERM, U-1127, 3 CNRS, UMR 7225, CATI (M. Chupin), Institut du Cerveau et de la Moelle Épinière, Sorbonne Université, Paris; INSERM UMR1027 (P.-J.O.), Université de Toulouse III Paul Sabatier; Centre Mémoire (CMRR) Distalz (F.P.), CHU, INSERM 1171, Université de Lille; Service de Gériatrie (O.H.), Hôpital Broca, Université Paris Descartes; Centre de Neurologie (C.P.), INSERM U1144, Cognitive Hôpital Lariboisière, Université de Paris; Department of Neurology, INSERM U1061, Clinical and Research Memory Center of Montpellier (A.G.), Gui de Chauliac Hospital, University of Montpellier; Institut de Neurosciences des Systèmes, CMMR, PACA Ouest (M. Ceccaldi), INSERM, CHU Timone APHM and Aix Marseille Université; Department of Geriatric Medicine (C.A.), Angers University Memory Clinic, Research Center on Autonomy and Longevity, UPRES EA 4638, Angers University Hospital, University of Angers, France; Department of Medical Biophysics (C.A.), Robarts Research Institute, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, Canada; Centre Mémoire Ressource et Recherche de Lyon (CMRR) (P.K.-S.), Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR5292, Hôpital des Charpennes, Hospices Civils de Lyon, Université de Lyon; Centre Mémoire de Ressources et de Recherches (Y.B.), CHU Dijon Bourgogne, EA7460, Université de Bourgogne, Dijon; Service de Neurologie Hôpital Saint-Louis AP-HP (C.B.), Paris; Departement de Neurologie (D.W.), UNIROUEN, INSERM U1245, CNR-MAJ, CHU de Rouen, Université de Normandie; CMRR Grenoble Arc Alpin (M.S.), CHU Grenoble; CMRR (E.B.), University Hospital Tours; Centre de Résonance Magnétique des Systèmes Biologiques (I.B.-M.), UMR 5536 Université de Bordeaux/CNRS; and Memory Resource and Research Centre of Clermont-Ferrand (I.J.), CHU de Clermont-Ferrand, Clermont Auvergne University, Clermont-Ferrand, France.
Objective:
To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition.
Methods:
The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aβ42/Aβ40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders.
Results:
There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: -0.061, 95% confidence interval: -0.089, -0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning.
Conclusion:
In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.
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