Cognitive Phenotyping and Interpretation of Alzheimer Blood Biomarkers
Authors: Vincent Bouteloup, Nicolas Villain, Jean Sebastien Vidal, Fernando Gonzalez-Ortiz, Idil Yuksekel, Cristiano Santos, Susanna Schraen-Maschken, Isabelle Pellegrin, Sylvain Lehmann, Kaj Blennow, Geneviève Chêne, Olivier Hanon, Carole Dufouil, Vincent Planche, Isabelle Addra, Michèle Allard, Sandrine Andrieu, Pierre Anthony, Christine Astier, Alexandre Augier, Nicolas Auguste, Sophie Auriacombe, John Avet, Chabha Azouani, Olivier Bailon, Anna-Chloé Balageas, Fabrice-Guy Barral, Jean Barré, Annick Barthelaix, Catherine Bayle, Olivier Beauchet, Serge Belliard, Catherine Belin, Samia Belkacem, Hugo Bertin, Douraied Ben Salem, Karim Bennys, Géraldine Bera, Eric Berger, Marc G Berger, Emilie Bergouin, François Bertin-Hugault, Guillaume Bertrand, François-Xavier Bertrand, Catherine Beze, Valérie Boilet, Stéphanie Bombois, Alain Bonafé, Yasmina Boudali, Hatem Bouhladour, Clémence Boully, Isabelle Bourdel-Marchasson, Vincent Bouteloup, Claire Boutet, Christophe Bouvier, Laïla Bouzid, Serge Bracard, Antoine Brangier, Pierre-Yves Brillet, Laure Caillard, Fabienne Calvas, Agnès Camus, Vincent Camus, Sandrine Canaple, Alexandre Cantan, Antoine Carpentier, Pascaline Cassagnaud, Françoise Cattin, Ludivine Chamard, Stéphane Chanalet, Mathieu Chastan, Sophie Chauvelier, Valérie Chauvire, Geneviève Chêne, Samia Cheriet, Marie Chupin, Anthony Clotagatide, Emmanuel Cognat, Lora Cohen, Jean-Marc Constans, Marie-Hélène Coste, Jean-Philippe Cottier, François Cotton, Isabelle Couret, Olivier-François Couturier, Pascale Cowppli-Bony, Véronique Cressot, Benjamin Crétin, Keren Danaila, Jacques Darcourt, Jean-François Dartigues, Ana-Maria Dascalita, Renaud David, Samuel David, Xavier De Petigny, Delphine De Verbizier-Lonjon, Marielle Decousus, Isabelle Defouilloy, Christine Delmaire, Julien Delrieu, Catherine Demuyinck, Vincent Deramecourt, Hervé Deramond, Thomas Desmidt, Marie-Dominique Desruet, Julien Detour, Agnès Devendeville, Mira Didic, Sonia Djober, Maritchu Doireau, Antonio Dos Santos, Patrice Douillet, Foucaud Du Boisgueheneuc, Delphine Dubail, Laure Ducroq-Ducastaing, Carole Dufouil, Cynthia Dumoulin, Julien Dumurgier, Diane Dupuy, Emmanuelle Duron, Inna Dygai-Cochet, Véronique Eder, Fouzia El Mountassir, Stéphane Epelbaum, Julie Erraud, Frédérique Etcharry-Bouyx, Daniel Fagret, Catherine Faisant, Karim Farid, Denis Fédérico, Olivier Felician, Philippe Fernandez, Pacôme Fosse, Alexandra Foubert-Samier, Isabelle Franck, Pauline Gaffez, Monique Galitzky, Céline Gallazzini-Crepin, Radka Gantchev, Laurence Garbarg-Chenon, Guillaume Gautier, Emmanuel Gerardin, Claire Gervais, Jean-Claude Getenet, Nadine Girard, Fabienne Giraud, Chantal Girtanner, Valérie Gissot, Caroline Grangeon, Leslie Grasset, Daniel Grucker, Eric Guedj, Claude Gueriot, Yves Guilhermet, Rémy Guillevin, Marie Odile Habert, Sophie Haffen, Didier Hannequin, Sandrine Harston, Anne Hitzel, Caroline Hommet, Claude Hossein-Foucher, Fabrice Hubele, Agnès Jacquin-Piques, Betty Jean, Delphine Jean, Joanne Jenn, Laure Joly, Thérèse Jonveaux, Adrien Julian, Anisse Karoun, Aurélie Kas, Anna Kearney-Schwartz, Alice Keles, Antony Kelly, Nathalie Keromnes, Lejla Koric, Maxime Locatelli, Alexandre Krainik, Stéphane Kremer, Florian Labourée, Franck Lacoeuille, Emilie Laheranne, Francoise Lala, Chantal Lamy, Jean-Louis Laplanche, Cyrille Launay, Lisa Le Scouarnec, Stéphane Lehericy, Sylvain Lehmann, Hermine Lenoir, Marcel Levy, Stéphanie Libercier, Julie Lidier, Marie-Anne Mackowiak-Cordoliani, Eloi Magnin, Zaza Makaroff, Jean-François Mangin, Athina Marantidou, Isabelle Marcet, Olivier Marcy, Cécilia Marelli, Sophie Marilier, Idalie Martin, Olivier Martinaud, Catherine Martin-Hunyadi, Aïcha Medjoul, Lauralee Menier, Isabelle Merlet, Danielle Mestas, Marc-Etienne Meyer, Jean-Marc Michel, Agnès Michon, Isabelle Migeon-Duballet, Sophie Mohr, Karl Mondon, Clément Morgat, Véronique Moullart, Christian Moussard, Aurélie Mouton, Izzie Jacques Namer, Georges Niewiadomski, Guillaume Nivaggioni, Marie Noblet, Michel Nonent, Fati Nourhashemi, Hélène Oesterle, Galdric Orvoen, Pierre-Jean Ousset, Amandine Pallardy, Claire Paquet, Pierre-Yves Pare, Anne Pasco, Pierre Payoux, Cécile Pays, Isabelle Pellegrin, Rémy Perdrisot, Bertille Perin, Christine Perret-Guillaume, Sophie Perusat, Grégory Petyt, Nathalie Philippi, Geneviève Pinganaud, Vincent Planche, Matthieu Plichart, Gabriel Pop, Michèle Puel, Mathieu Queneau, Solène Querellou, Muriel Quillard-Muraine, Valérie Quipourt, Chloé Rachez, Micheline Razzouk-Cadet, Anne-Sophie Rigaud, Hélène Robin-Ismer, Mathieu Rodallec, Yves Rolland, Adeline Rollin-Sillaire, Stéphanie Roseng, Olivier Rouaud, Caroline Roubaud, Isabelle Rouch, Julie Roux, Guillaume Sacco, Pierre-Yves Salaun, François Salmon, Alicia Sanchez, Maria-Joao Santiago-Ribeiro, Alain Sarciron, Nathalie Sastre-Hengan, Mathilde Sauvée, Helen Savarieau, Christian Scheiber, Anne-Marie Schneider, Franck Semah, Amélie Serra, Marie-Laure Seux, Hélène Sordet-Guépet, Maria Eugenia Soto, Sullivan Marie, Mathieu Tafani, Jean-Yves Tanguy, Michael Taroux, Marc Teichmann, Catherine Terrat, Jamila Thabet, Claire Thalamas, Nathalie Thierry, Catherine Thomas-Anterion, Anne-Cécile Troussière, Renata Ursu, Pierre Vera, Martine Vercelletto, Olivier Vercruysse, Antoine Verger, Philippe Viau, Marie-Neige Videau, Thierry Voisin, Nathalie Wagemann, Aziza Waissi-Sediq, Jing Xie, Nathanaëlle Yeni, Michel Zanca, Jean Zinszner, Olivier Hanon, Frédéric Blanc, Audrey Gabelle, Jacques Touchon, Xavier Delbeuck, Florence Moulin, Florence Latour, Sophie Pichierri, Galdric Orvoën, Evelyne Galbrun, Giovanni Castelnovo, Lisette Volpe-Gillot, Florien Labourée, Françoise Lala, Bruno Vellas, Eliana Alonso, Foucaud du Boisgueheneuc, Laurence Hugonot-Diener, Yann Spivac, Joël Belmin, Philippe Robert , Thierry Dantoine, David Wallon, Nathalie Sastre, Jean-Luc Novella, Gabiel Abitbol, Nathalie Schwald, François Sellal, Marie-Ange Cariot, Mohamed Abdellaoui, Sarah Benisty , Salim Gherabli, Frédéric Bloch, Nathalie Charasz, Jean-Yves Gaubert, Olivier Guerin, Jacques Boddaert , Marc Paccalin, Marie-Anne Mackowiak, Marie-Thérèse Rabus, Athanase Benetos, Candice Picard, Céline Guillemaud, Gilles Berrut, Jaques Hugon, JeanPhilippe David, Marion Paulin , Pierre Vandel, Sylvie Pariel, Anne Chawakilian, Léna Kermanac’h, Anne-Cécile Troussiere, Cécile Adam, Elena Paillaud, Hélène Briault, Isabelle Saulnier, Marie-Agnès Picat, Marie Laurent, Olivier Godefroy, Rezki Daheb, Djamila Krabchi, Jean-Sébastien Vidal, Edouard Chaussade, Christiane Baret-Rose, Bernadette Allinquant, Susanna Schraen-Maschke
Journal: JAMA Neurology (2025)

Importance Blood phosphorylated tau 217 (p-tau217) showed good performance in predicting brain amyloidosis. However, the importance of detailed cognitive phenotyping in patients without dementia when interpreting p-tau217 results remains unclear. Objective To assess whether accuracy, negative predictive value (NPV), and positive predictive value (PPV) in predicting brain amyloidosis using p-tau217 varies across clinical presentations in patients without dementia. Design, Setting, and Participants The study design included 2 observational, prospective cohort studies: The Cohort of Outpatients From French Research Memory Centers in Order to Improve Knowledge on Alzheimer’s Disease and Related Disorders (MEMENTO), with enrollment from 2011 to 2014 and 5 years of follow-up, and the Biomarker of Amyloid Peptide and Alzheimer’s Disease Risk (BALTAZAR) cohort study, with enrollment from 2010 to 2015 and 3 years of follow-up. Both are multicenter cohorts conducted in French memory clinics. Participants without dementia were included for analysis if they had baseline blood p-tau217 measurement and a known amyloid status through cerebrospinal fluid amyloid β (Aβ)–42/Aβ-40 ratio or positron emission tomography. They presented with either subjective cognitive impairment (SCI), mild cognitive impairment (MCI) with a common Alzheimer disease (AD) phenotype (cAD-MCI: amnestic syndrome of hippocampal type, posterior cortical atrophy, or logopenic primary progressive aphasia), or MCI with uncommon AD or other phenotypes (uAD-MCI). Data were analyzed from May to September 2024. Exposures Blood p-tau217 concentrations. Main Outcomes and Measures Brain amyloidosis probabilities were derived from p-tau217 logistic regressions including age, gender, and APOE genotype. Published and internally developed cut points with 90% sensitivity and specificity were used. Results A total of 776 participants from the MEMENTO cohort (N = 2323 participants) and 193 participants from the BALTAZAR cohort (N = 1040) were included in this analysis. In the MEMENTO cohort (median [IQR] age, 71 [65-76] years; 444 female [57%]), brain amyloidosis prevalence was 16.5% (20 of 121) in SCI, 45.9% (78 of 170) in cAD-MCI, and 24.5% (119 of 485) in uAD-MCI. Area under the receiver operating characteristic curve for predicting brain amyloidosis with p-tau217 models was 0.78 (95% CI, 0.66-0.89), 0.91 (95% CI, 0.86-0.95), and 0.87 (95% CI, 0.84-0.91) in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. External cut points resulted in a PPV of 60.0%, 90.0%, and 74.5% in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. NPV ranged from 84.2% to 90.2%. With internally developed cut points, PPVs were 52.6%, 84.0%, and 72.3% in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. NPVs were high (91.7%-94.6%) in all subgroups. Rates of incident dementia strongly increased with the probability of brain amyloidosis in the cAD-MCI subgroup. Replicated analyses in the BALTAZAR cohort provided similar results. Conclusions and Relevance Results from 2 clinical cohorts suggest that amyloid prevalence varied across cognitive phenotypes and was associated with the diagnostic performance of blood p-tau217 models to determine brain amyloidosis. Comprehensive cognitive phenotyping beyond the basic characterization of SCI, MCI, or dementia should accompany the use of blood biomarkers in clinical practice to avoid misdiagnosis due to false positives.