Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes
Authors: Sogorb-Esteve Aitana , Weiner Sophia , Simrén Joel , Swift Imogen J. , Bocchetta Martina , Todd Emily G. , Cash David M. , Bouzigues Arabella , Russell Lucy L. , Foster Phoebe H. , Ferry-Bolder Eve , van Swieten John C. , Jiskoot Lize C. , Seelaar Harro , Sanchez-Valle Raquel , Laforce Robert , Graff Caroline , Galimberti Daniela , Vandenberghe Rik , de Mendonça Alexandre , Tiraboschi Pietro , Santana Isabel , Gerhard Alexander , Levin Johannes , Sorbi Sandro , Otto Markus , Pasquier Florence , Ducharme Simon , Butler Chris R. , Le Ber Isabelle , Finger Elizabeth , Tartaglia Maria Carmela , Masellis Mario , Rowe James B. , Synofzik Matthis , Moreno Fermin , Borroni Barbara , GENFI  , Blennow Kaj , Zetterberg Henrik , Rohrer Jonathan D. , Gobom Johan , Thomas David L. , Cope Thomas , Rittman Timothy , Benussi Alberto , Premi Enrico , Gasparotti Roberto , Archetti Silvana , Gazzina Stefano , Cantoni Valentina , Arighi Andrea , Fenoglio Chiara , Scarpini Elio , Fumagalli Giorgio , Borracci Vittoria , Rossi Giacomina , Giaccone Giorgio , Di Fede Giuseppe , Caroppo Paola , Tiraboschi Pietro , Prioni Sara , Radaaelli Veronica , Tang-Wai David , Rogaeva Ekaterina , Castelo-Branco Michel , Freedman Morris , Keren Ron , Black Sandra , Mitchell Sara , Shoesmith Christen , Bartha Robart , Rademakers Rosa , Poos Jackie , Papma Janne M. , Giannini Lucia , van Minkelen Rick , Pijnenburg Yolande , Nacmias Benedetta , Ferrari Camilla , Polito Cristina , Lombardi Gemma , Bessi Valentina , Veldsman Michele , Andersson Christin , Thonberg Hakan , Öijerstedt Linn , Jelic Vesna , Thompson Paul , Langheinrich Tobias , Llado Albert , Antonell Anna , Olives Jaume , Balasa Mircea , Bargalló Nuria , Borrego-Écija Sergi , Verdelho Ana , Maruta Carolina , Ferreira Catarina B. , Miltenberger Gabriel , do Couto Frederico Simões , Gabilondo Alazne , Villanua Jorge , Cañada Marta , Tainta Mikel , Zulaica Miren , Barandiaran Myriam , Alves Patricial , Bender Benjamin , Wilke Carlo , Graf Lisa , Vogels Annick , Vandenbulcke Mathieu , van Damme Philip , Buffaerts Rose , Poesen Koen , Rosa-Neto Pedro , Gauthier Serge , Camuzat Agnès , Brice Alexis , Bertrand Anne , Funkiewiez Aurélie , Rinaldi Daisy , Saracino Dario , Colliot Olivier , Sayah Sabrina , Prix Catharina , Wlasich Elisabeth , Wagemann Olivia , Loosli Sandra , Schönecker Sonja , Hoegen Tobias , Lombardi Jolina , Anderl-Straub Sarah , Rollin Adeline , Kuchcinski Gregory , Bertoux Maxime , Lebouvier Thibaud , Deramecourt Vincent , Santiago Beatriz , Duro Diana , Leitão Maria João , Almeida Maria Rosario , Tábuas-Pereira Miguel , Afonso Sónia 
Published: February 2025

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44
C9orf72
, 38
GRN
, and 25
MAPT
) and 55 symptomatic (27
C9orf72
, 17
GRN
, and 11
MAPT
) mutation carriers as well as 76 mutation-negative controls (“noncarriers”). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer’s disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in
MAPT
carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.