Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based
Vincent Planche1, Vincent Bouteloup2, Isabelle Pellegrin2
1From the Univ. Bordeaux (V.P.), CNRS UMR 5293, Institut des Maladies Neurodégénératives; CHU de Bordeaux (V.P.), Pôle de Neurosciences Cliniques, Centre Mémoire de Ressources et de Recherche; Univ. Bordeaux (V.B., G.C., C.D.), Inserm U1219, PHARes Team, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED); CHU Bordeaux (V.B., G.C., C.D.), CIC 1401 EC, Pôle Santé Publique; CHU de Bordeaux (I.P.), Département d'Immunologie et d'Immunogénétique; Univ. Paris-Saclay (J.-F.M.), CEA, CNRS, Baobab UMR9027, Neurospin, CATI Multicenter Neuroimaging Platform, US52, UAR 9031, Gif-sur-Yvette; Sorbonne-Université (B.D.), Service des Maladies Cognitives et Comportementales et Institut de La Mémoire et de La Maladie d'Alzheimer (IM2A), Hôpital de La Salpêtrière, AP-PH, Paris; Univ. Toulouse (P.-J.O.), Inserm U1027, Gérontopôle, Departement de Gériatrie, CHU Purpan, Toulouse; Univ. Lille (F.P.), Inserm U1171, Centre Mémoire de Ressources et de Recherche, CHU Lille, DISTAlz, Lille; Univ. Strasbourg (F.B.), CNRS, ICube Laboratory, UMR 7357, Fédération de Médecine Translationnelle de Strasbourg, Centre Mémoire de Ressources et de Recherche, Pôle de Gériatrie, Strasbourg; Univ. Paris (C.P.), Inserm U1144, Groupe Hospitalier Lariboisière Fernand-Widal, AP-HP; Univ. Paris Cité (O.H.), EA 4468, AP-HP, Hôpitaux Universitaires Paris Centre, Service de Gériatrie, Hôpital Broca; CHU de Montpellier (K.B.), Pôle de Neurosciences, Département de Neurologie, Centre Mémoire de Ressources et de Recherche, Montpellier; Univ. Aix Marseille (M.C.), Inserm UMR 1106, Institut de Neurosciences des Systèmes, Centre Mémoire de Ressources et de Recherche, Département de Neurologie et de Neuropsychologie, AP-HM, Marseille; Univ. Angers (C.A.), UPRES EA 4638, Centre Mémoire de Ressources et de Recherche, Département de Gériatrie, CHU d'Angers, Angers; Univ. Lyon (P.K.-S.), Inserm U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Centre Mémoire Ressource et Recherche de Lyon (CMRR), Hôpital des Charpennes, Hospices Civils de Lyon; Univ. Picardie (O.G.), UR UPJV4559, Laboratoire de Neurosciences Fonctionnelles et Pathologies, Service de Neurologie, CHU Amiens; Univ. Normandie (D.W.), UNIROUEN, Inserm U1245, Departement de Neurologie, CNR-MAJ, CHU de Rouen; Centre Mémoire de Ressources et de Recherche Grenoble Arc Alpin (M.S.), Pôle de Psychiatrie et Neurologie, CHU Grenoble Alpes; CHU de Nantes (C.B.-B.), Département de Neurologie, Centre Mémoire de Ressources et Recherche, Nantes; Univ. Bordeaux (I.B.-M.), CNRS UMR 5536, Centre de Résonance Magnétique des Systèmes Biologiques, Pôle de Gérontologie Clinique, CHU de Bordeaux; and Univ. Clermont Auvergne (I.J.), CNRS, CHU Clermont-Ferrand, Centre Mémoire de Ressources et de Recherche, Service de Psychiatrie de L'Adulte A et Psychologie Médicale, Clermont Auvergne INP, Institut Pascal, Clermont-Ferrand. vincent.planche@u-bordeaux.fr.
Background And Objective:
Blood biomarkers for Alzheimer disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. Our aim was to test their utility in clinical practice, from a multicentric unselected prospective cohort where patients presented with a large spectrum of cognitive deficits or complaints.
Methods:
The MEMENTO cohort enrolled 2,323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, MRI, and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood Aβ42/40 ratio, total tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period.
Results:
Overall, 2,277 individuals had at least 1 baseline blood biomarker available (n = 357 for CSF subsample, n = 649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total tau were mildly correlated with their equivalence in the CSF (r = 0.33 to 0.46, p < 0.0001) and were associated with amyloid-PET status (p < 0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (area under the curve = 0.74 [95% CI = 0.69; 0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood Aβ42/40 was less efficient than CSF Aβ42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index = 0.73 [95% CI = 0.69; 0.77]); its accuracy was higher in patients with clinical dementia rating (CDR) = 0 (c-index = 0.83 [95% CI = 0.69; 0.97]) than in patients with CDR = 0.5 (c-index = 0.70 [95% CI = 0.66; 0.74]). A "clinical" reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index = 0.88 [95% CI = 0.86-0.91] and performance increased to 0.90 [95% CI = 0.88; 0.92] when adding blood p181-tau + Aβ42/40. A "research" reference model (clinical model + apolipoprotein E genotype and AD signature on MRI) had a c-index = 0.91 [95% CI = 0.89-0.93] increasing to 0.92 [95% CI = 0.90; 0.93] when adding blood p181-tau + Aβ42/40. Chronic kidney disease and vascular comorbidities did not affect predictive performances.
Discussion:
In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors.
More Related Videos
06:23The 4 Mountains Test: A Short Test of Spatial Memory with High Sensitivity for the Diagnosis of Pre-dementia Alzheimer's Disease
Published on: October 13, 2016
07:20Dried Blood Spot Collection of Health Biomarkers to Maximize Participation in Population Studies
Published on: January 28, 2014
Related Concept Videos
01:26Alzheimer's Disease: Overview
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
01:30Dementia
The progression of dementia is generally gradual....