MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints
Authors: Vergallo Andrea , Lista Simone , Zhao Yuhai , Lemercier Pablo , Teipel Stefan J. , Potier Marie-Claude , Habert Marie-Odile , Dubois Bruno , Lukiw Walter J. , Hampel Harald ,   for the INSIGHT-preAD study group, Bakardjian Hovagim , Benali Habib , Bertin Hugo , Bonheur Joel , Boukadida Laurie , Boukerrou Nadia , Cavedo Enrica , Chiesa Patrizia , Colliot Olivier , Dubois Bruno , Dubois Marion , Epelbaum Stéphane , Gagliardi Geoffroy , Genthon Remy , Habert Marie-Odile , Hampel Harald , Houot Marion , Kas Aurélie , Lamari Foudil , Levy Marcel , Lista Simone , Metzinger Christiane , Mochel Fanny , Nyasse Francis , Poisson Catherine , Potier Marie-Claude , Revillon Marie , Santos Antonio , Andrade Katia Santos , Sole Marine , Surtee Mohmed , de Schotten Michel Thiebaut , Vergallo Andrea , Younsi Nadjia , Dubois Bruno ,   the Alzheimer Precision Medicine Initiative (APMI), Afshar Mohammad , Aguilar Lisi Flores , Akman-Anderson Leyla , Arenas Joaquín , Ávila Jesús , Babiloni Claudio , Baldacci Filippo , Batrla Richard , Benda Norbert , Black Keith L. , Bokde Arun L. W. , Bonuccelli Ubaldo , Broich Karl , Cacciola Francesco , Caraci Filippo , Caruso Giuseppe , Castrillo Juan , Cavedo Enrica , Ceravolo Roberto , Chiesa Patrizia A. , Corbo Massimo , Corvol Jean-Christophe , Cuello Augusto Claudio , Cummings Jeffrey L. , Depypere Herman , Duggento Andrea , Emanuele Enzo , Escott-Price Valentina , Federoff Howard , Ferretti Maria Teresa , Fiandaca Massimo , Frank Richard A. , Garaci Francesco , Geerts Hugo , Giacobini Ezio , Giorgi Filippo S. , Goetzl Edward J. , Graziani Manuela , Haberkamp Marion , Hänisch Britta , Herholz Karl , Hernandez Felix , Imbimbo Bruno P. , Kapogiannis Dimitrios , Karran Eric , Kiddle Steven J. , Kim Seung H. , Koronyo Yosef , Koronyo-Hamaoui Maya , Langevin Todd , Lehéricy Stéphane , Llavero Francisco , Lorenceau Jean , Lucía Alejandro , Mango Dalila , Mapstone Mark , Neri Christian , Nisticò Robert , O’Bryant Sid E. , Palermo Giovanni , Perry George , Ritchie Craig , Rossi Simone , Saidi Amira , Santarnecchi Emiliano , Schneider Lon S. , Sporns Olaf , Toschi Nicola , Valenzuela Pedro L. , Vellas Bruno , Verdooner Steven R. , Villain Nicolas , Giudici Kelly Virecoulon , Watling Mark , Welikovitch Lindsay A. , Woodcock Janet , Younesi Erfan , Zugaza José L. 
Published: January 2021

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs—miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic 18F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and 18F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways.