Low circulating adropin concentrations predict increased risk of cognitive decline in community-dwelling older adults
Authors: Aggarwal Geetika , Morley John E. , Vellas Bruno , Nguyen Andrew D. , Butler Andrew A. ,   for the MAPT/DSA Group, Guyonnet Sophie , Carrié Isabelle , Brigitte Lauréane , Faisant Catherine , Lala Françoise , Delrieu Julien , Villars Hélène , Combrouze Emeline , Badufle Carole , Zueras Audrey , Andrieu Sandrine , Cantet Christelle , Morin Christophe , Van Kan Gabor Abellan , Dupuy Charlotte , Rolland Yves , Caillaud Céline , Ousset Pierre-Jean , Lala Françoise , Willis Sherry , Belleville Sylvie , Gilbert Brigitte , Fontaine Francine , Dartigues Jean-François , Marcet Isabelle , Delva Fleur , Foubert Alexandra , Cerda Sandrine , Marie-Noëlle-Cuffi  , Costes Corinne , Rouaud Olivier , Manckoundia Patrick , Quipourt Valérie , Marilier Sophie , Franon Evelyne , Bories Lawrence , Pader Marie-Laure , Basset Marie-France , Lapoujade Bruno , Faure Valérie , Tong Michael Li Yung , Malick-Loiseau Christine , Cazaban-Campistron Evelyne , Desclaux Françoise , Blatge Colette , Dantoine Thierry , Laubarie-Mouret Cécile , Saulnier Isabelle , Clément Jean-Pierre , Picat Marie-Agnès , Bernard-Bourzeix Laurence , Willebois Stéphanie , Désormais Iléana , Cardinaud Noëlle , Bonnefoy Marc , Livet Pierre , Rebaudet Pascale , Gédéon Claire , Burdet Catherine , Terracol Flavien , Pesce Alain , Roth Stéphanie , Chaillou Sylvie , Louchart Sandrine , Sudres Kristel , Lebrun Nicolas , Barro-Belaygues Nadège , Touchon Jacques , Bennys Karim , Gabelle Audrey , Romano Aurélia , Touati Lynda , Marelli Cécilia , Pays Cécile , Robert Philippe , Le Duff Franck , Gervais Claire , Gonfrier Sébastien , Gasnier Yannick , Bordes Serge , Begorre Danièle , Carpuat Christian , Khales Khaled , Lefebvre Jean-François , El Idrissi Samira Misbah , Skolil Pierre , Salles Jean-Pierre , Dufouil Carole , Lehéricy Stéphane , Chupin Marie , Mangin Jean-François , Bouhayia Ali , Allard Michèle , Ricolfi Frédéric , Dubois Dominique , Martel Marie Paule Bonceour , Cotton François , Bonafé Alain , Chanalet Stéphane , Hugon Françoise , Bonneville Fabrice , Cognard Christophe , Chollet François , Payoux Pierre , Voisin Thierry , Delrieu Julien , Peiffer Sophie , Hitzel Anne , Allard Michèle , Zanca Michel , Monteil Jacques , Darcourt Jacques , Molinier Laurent , Derumeaux Hélène , Costa Nadège , Perret Bertrand , Vinel Claire , Caspar-Bauguil Sylvie , Olivier-Abbal Pascale , Andrieu Sandrine , Cantet Christelle , Coley Nicola 
Published: May 2023

Abstract
The secreted peptide adropin is highly expressed in human brain tissues and correlates with RNA and proteomic risk indicators for dementia. Here we report that plasma adropin concentrations predict risk for cognitive decline in the Multidomain Alzheimer Preventive Trial (ClinicalTrials.gov Identifier, NCT00672685; mean age 75.8y, SD = 4.5 years, 60.2% female, n = 452). Cognitive ability was evaluated using a composite cognitive score (CCS) that assessed four domains: memory, language, executive function, and orientation. Relationships between plasma adropin concentrations and changes in CCS (∆CCS) were examined using Cox Proportional Hazards Regression, or by grouping into tertiles ranked low to high by adropin values and controlling for age, time between baseline and final visits, baseline CCS, and other risk factors (e.g., education, medication, APOE4 status). Risk of cognitive decline (defined as a ∆CCS of − 0.3 or more) decreased with increasing plasma adropin concentrations (hazard ratio = 0.873, 95% CI 0.780–0.977, P = 0.018). Between adropin tertiles, ∆CCS was significantly different (P = 0.01; estimated marginal mean ± SE for the 1st to 3rd tertile, − 0.317 ± 0.064; − 0.275 ± 0.063; − 0.042 ± 0.071; n = 133,146, and 130, respectively; P < 0.05 for 1st vs. 2nd and 3rd adropin tertiles). Normalized plasma Aß42/40 ratio and plasma neurofilament light chain, indicators of neurodegeneration, were significantly different between adropin tertile. These differences were consistent with reduced risk of cognitive decline with higher plasma adropin levels. Overall, these results suggest cognitive decline is reduced in community-dwelling older adults with higher circulating adropin levels. Further studies are needed to determine the underlying causes of the relationship and whether increasing adropin levels can delay cognitive decline.