Insulin-like growth factor binding protein-2 in at-risk adults and autopsy-confirmed Alzheimer brains
Authors: Quesnel Marc James , Labonté Anne , Picard Cynthia , Zetterberg Henrik , Blennow Kaj , Brinkmalm Ann , Villeneuve Sylvia , Poirier Judes ,   for the Alzheimer’s Disease Neuroimaging Initiative, Weiner Michael W , Aisen Paul , Petersen Ronald , Weiner Michael W , Aisen Paul , Petersen Ronald , Jack Clifford R , Jagust William , Trojanowki John Q , Toga Arthur W , Beckett Laurel , Green Robert C , Saykin Andrew J , Morris John C , Perrin Richard J , Shaw Leslie M , Khachaturian Zaven , Carrillo Maria , Potter William , Barnes Lisa , Bernard Marie , González Hector , Ho Carole , Hsiao John K , Jackson Jonathan , Masliah Eliezer , Masterman Donna , Okonkwo Ozioma , Perrin Richard , Ryan Laurie , Silverberg Nina , Fleisher Adam , Weiner Michael W , Sacrey Diana Truran , Fockler Juliet , Conti Cat , Veitch Dallas , Neuhaus John , Jin Chengshi , Nosheny Rachel , Ashford Miriam , Flenniken Derek , Kormos Adrienne , Green Robert C , Montine Tom , Conti Cat , Petersen Ronald , Aisen Paul , Rafii Michael , Raman Rema , Jimenez Gustavo , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Cabrera Yuliana , Walter Sarah , Miller Garrett , Coker Godfrey , Clanton Taylor , Hergesheimer Lindsey , Smith Stephanie , Adegoke Olusegun , Mahboubi Payam , Moore Shelley , Pizzola Jeremy , Shaffer Elizabeth , Sloan Brittany , Beckett Laurel , Harvey Danielle , Donohue Michael , Jack Clifford R , Forghanian-Arani Arvin , Borowski Bret , Ward Chad , Schwarz Christopher , Jones David , Gunter Jeff , Kantarci Kejal , Senjem Matthew , Vemuri Prashanthi , Reid Robert , Fox Nick C , Malone Ian , Thompson Paul , Thomopoulos Sophia I , Nir Talia M , Jahanshad Neda , DeCarli Charles , Knaack Alexander , Fletcher Evan , Harvey Danielle , Tosun-Turgut Duygu , Chen Stephanie Rossi , Choe Mark , Crawford Karen , Yushkevich Paul A , Das Sandhitsu , Jagust William , Koeppe Robert A , Reiman Eric M , Chen Kewei , Mathis Chet , Landau Susan , Morris John C , MD Richard Perrin , Cairns Nigel J , Householder Erin , Franklin Erin , R Haley Bernhardt , Taylor-Reinwald Louis Lisa , Shaw Leslie M , Trojanowki John Q , Korecka Magdalena , Figurski Michal , Toga Arthur W , Crawford Karen , Neu Scott , Saykin Andrew J , Nho Kwangsik , Risacher Shannon L , Apostolova Liana G , Shen Li , Foroud Tatiana M , Nudelman Kelly , Faber Kelley , Wilmes Kristi , Weiner Michael W , Thal Leon , Khachaturian Zaven , Hsiao John K , Silbert Lisa C , Lind Betty , Crissey Rachel , Kaye Jeffrey A , Carter Raina , Dolen Sara , Quinn Joseph , Schneider Lon S , Pawluczyk Sonia , Becerra Mauricio , Teodoro Liberty , Dagerman Karen , Spann Bryan M , Brewer James , Vanderswag Helen , Fleisher Adam , Ziolkowski Jaimie , Heidebrink Judith L , Zbizek-Nulph M S Lisa , Lord Joanne L , Zbizek-Nulph Lisa , Petersen Ronald , Mason Sara S , Albers Colleen S , Knopman David , Johnson Kris , Villanueva-Meyer Javier , Pavlik Valory , Pacini Nathaniel , Lamb Ashley , Kass Joseph S , Doody Rachelle S , Shibley Victoria , Chowdhury Munir , Dang Mimi , Stern Yaakov , Honig Lawrence S , Mintz Akiva , Ances Beau , Morris John C , Winkfield David , Carroll Maria , Stobbs-Cucchi Georgia , Oliver Angela , Creech Mary L , Mintun Mark A , Schneider Stacy , Geldmacher David , Love Marissa Natelson , Griffith Randall , Clark David , Brockington John , Marson Daniel , Grossman Hillel , Goldstein Martin A , Greenberg Jonathan , Mitsis Effie , Shah Raj C , Lamar Melissa , Duara Ranjan , Greig-Custo Maria T , Rodriguez Rosemarie , Albert Marilyn , Onyike Chiadi , Farrington Leonie , Rudow Scott , Brichko Rottislav , Kielb Stephanie , Smith Amanda , Raj Balebail Ashok , Fargher Kristin , Sadowski Martin , Wisniewski Thomas , Shulman Melanie , Faustin Arline , Rao Julia , Castro Karen M , Ulysse Anaztasia , Chen Shannon , Sheikh Mohammed O , Singleton-Garvin Jamika , Doraiswamy P Murali , Petrella Jeffrey R , James Olga , Wong Terence Z , Borges-Neto Salvador , Karlawish Jason H , Wolk David A , Vaishnavi Sanjeev , Clark Christopher M , Arnold Steven E , Smith Charles D , Jicha Gregory A , El Khouli Riham , Raslau Flavius D , Lopez Oscar L , Oakley MaryAnn , Simpson Donna M , Porsteinsson Anton P , Martin Kim , Kowalski Nancy , Keltz Melanie , Goldstein Bonnie S , Makino Kelly M , Ismail M Saleem , Brand Connie , Thai Gaby , Pierce Aimee , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Kelley Brendan , Nguyen Trung , Womack Kyle , Mathews Dana , Quiceno Mary , Levey Allan I , Lah James J , Hajjar Ihab , Cellar Janet S , Burns Jeffrey M , Swerdlow Russell H , Brooks William M , Silverman Daniel H S , Kremen Sarah , Apostolova Liana , Tingus Kathleen , Lu H , Bartzokis George , Woo Ellen , Teng Edmond , Graff-Radford Neill R , Parfitt Francine , Poki-Walker Kim , Farlow Martin R , Hake Ann Marie , Matthews Brandy R , Brosch Jared R , Herring Scott , van Dyck Christopher H , Mecca Adam P , Mecca Adam P , Good Susan P , MacAvoy Martha G , Carson Richard E , Varma Pradeep , Chertkow Howard , Vaitekunis Susan , Hosein Chris , Black Sandra , Stefanovic Bojana , Heyn Chris (Chinthaka) , Hsiung Ging-Yuek Robin , Kim Ellen , Mudge Benita , Sossi Vesna , Feldman Howard , Assaly Michele , Finger Elizabeth , Pasternak Stephen , Rachinsky Irina , Kertesz Andrew , Drost Dick , Rogers John , Grant Ian , Muse Brittanie , Rogalski Emily , Robson Jordan , Mesulam M-Marsel , Kerwin Diana , Wu Chuang-Kuo , Johnson Nancy , Lipowski Kristine , Weintraub Sandra , Bonakdarpour Borna , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Rosen Howard J , Miller Bruce L , Perry David , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , MCCann Kelly , Poe Jessica , Sperling Reisa A , Johnson Keith A , Marshall Gad A , Yesavage Jerome , Taylor Joy L , Chao Steven , Coleman Jaila , White Jessica D , Lane Barton , Rosen Allyson , Tinklenberg Jared , Belden Christine M , Atri Alireza , Spann Bryan M , Clark Kelly A , Zamrini Edward , Sabbagh Marwan , Killiany Ronald , Stern Robert , Mez Jesse , Kowall Neil , Budson Andrew E , Obisesan Thomas O , Ntekim Oyonumo E , Wolday Saba , Khan Javed I , Nwulia Evaristus , Nadarajah Sheeba , Lerner Alan , Ogrocki Paula , Tatsuoka Curtis , Fatica Parianne , Fletcher Evan , Maillard Pauline , Olichney John , DeCarli Charles , Carmichael Owen , Bates Vernice , Capote Horacio , Rainka Michelle , Borrie Michael , Lee T-Y , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M , Perrin Allison , Burke Anna , Scharre Douglas W , Kataki Maria , Tarawneh Rawan , Kelley Brendan , Hart David , Zimmerman Earl A , Celmins Dzintra , Miller Delwyn D , Ponto Laura L Boles , Smith Karen Ekstam , Koleva Hristina , Shim Hyungsub , Nam Ki Won , Schultz Susan K , Williamson Jeff D , Craft M H S Suzanne , Cleveland Jo , Yang Mia , Sink Kaycee M , Ott Brian R , Drake Jonathan , Tremont Geoffrey , Daiello Lori A , Drake Jonathan D , Sabbagh Marwan , Ritter Aaron , Bernick Charles , Munic Donna , Mintz Akiva , O’Connelll Abigail , Mintzer Jacobo , Wiliams Arthur , Masdeu Joseph , Shi Jiong , Garcia Angelica , Sabbagh Marwan , Newhouse Paul , Potkin Steven , Salloway Stephen , Malloy Paul , Correia Stephen , Kittur Smita , Pearlson Godfrey D , Blank Karen , Anderson Karen , Flashman Laura A , Seltzer Marc , Hynes Mary L , Santulli Robert B , Relkin Norman , Chiang Gloria , Lee Athena , Lin Michael , Ravdin Lisa , Weiner Michael W , Aisen Paul , Petersen Ron , Weiner Michael W , Aisen Paul , Petersen Ronald , Green Robert C , Harvey Danielle , Jack Clifford R , Jagust William , Morris John C , Saykin Andrew J , Shaw Leslie M , Toga Arthur W , Trojanowki John Q , Neylan Thomas , Grafman Jordan , Green Robert C , Montine Tom , Weiner Michael W , Petersen Ronald , Aisen Paul , Jimenez Gustavo , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Walter Sarah , Adegoke Olusegun , Mahboubi Payam , Hergesheimer Lindsey , Danowski Sarah , Coker Godfrey , Clanton Taylor , Pizzola Jeremy , Shaffer Elizabeth , Nguyen-Barrera Catherine , Neylan Thomas , Hayes Jacqueline , Finley Shannon , Harvey Danielle , Donohue Michael , Jack Clifford R , Bernstein Matthew , Borowski Bret , Gunter Jeff , Senjem Matt , Kantarci Kejal , Ward Chad , Tosun-Turgut Duygu , Chen Rossi , Landau Susan , Koeppe Robert A , Foster Norm , Reiman Eric M , Chen Kewei , Morris John C , Perrin Richard J , Franklin Erin , Shaw Leslie M , Trojanowki John Q , Korecka Magdalena , Figurski Michal , Toga Arthur W , Crawford Karen , Neu Scott , Saykin Andrew J , Foroud Tatiana M , Potkin Steven , Shen Li , Faber Kelley , Kim Sungeun , Nho Kwangsik , Wilmes Kristi , Schneider Lon S , Pawluczyk Sonia , Becerra Mauricio , Teodoro Liberty , Dagerman Karen , Spann Bryan M , Brewer James , Vanderswag Helen , Fleisher Adam , Stern Yaakov , Honig Lawrence S , Mintz Akiva , Shah Raj C , Sood Ajay , Blanchard Kimberly S , Fleischman Debra , Arfanakis Konstantinos , Duara Ranjan , Varon Daniel , Greig Maria T , Doraiswamy P Murali , Petrella Jeffrey R , James Olga , Borges-Neto Salvador , Wong Terence Z , Porsteinsson Anton P , Goldstein Bonnie , Martin Kimberly S , Thai Gaby , Pierce Aimee , Reist Christopher , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Sadowsky Carl , Martinez Walter , Villena Teresa , Rosen Howard , Perry David , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , MCCann Kelly , Poe Jessica , Sperling Reisa A , Johnson Keith A , Marshall Gad , Belden Christine M , Atri Alireza , Spann Bryan M , Clark Kelly A , Zamrini Edward , Sabbagh Marwan , Obisesan Thomas O , Ntekim Oyonumo E , Wolday Saba , Nwulia Evaristus , Nadarajah Sheeba , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M , Peskind Elaine R , Petrie Eric C , Li Gail , Yesavage Jerome , Taylor Joy L , Chao Steven , Coleman Jaila , White Jessica D , Lane Barton , Rosen Allyson , Tinklenberg Jared , Lin Michael , Chiang Gloria , Ravdin Lisa , Relkin Norman , O’Connelll Abigail , Mintzer Jacobo , Wiliams Arthur , Mackin Scott , Aisen Paul , Raman Rema , Jimenez-Maggiora Gustavo , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Walter Sarah , Adegoke Olusegun , Mahboubi Payam , Mackin Scott , Weiner Michael W , Aisen Paul , Raman Rema , Jack Clifford R , Landau Susan , Saykin Andrew J , Toga Arthur W , DeCarli Charles , Koeppe Robert A , Green Robert C , Drake Erin , Weiner Michael W , Aisen Paul , Raman Rema , Donohue Mike , Mackin Scott , Nelson Craig , Bickford David , Butters Meryl , Zmuda Michelle , Jack Clifford R , Bernstein Matthew , Borowski Bret , Gunter Jeff , Senjem Matt , Kantarci Kejal , Ward Chad , Reyes Denise , Koeppe Robert A , Landau Susan , Toga Arthur W , Crawford Karen , Neu Scott , Saykin Andrew J , Foroud Tatiana M , Faber Kelley M , Nho Kwangsik , Nudelman Kelly N , Mackin Scott , Rosen Howard , Nelson Craig , Bickford David , Au Yiu Ho , Scherer Kelly , Catalinotto Daniel , Stark Samuel , Ong Elise , Fernandez Dariella , Butters Meryl , Zmuda Michelle , Lopez Oscar L , Oakley MaryAnn , Simpson Donna M ,   the PREVENT-AD Research Group, Javanray Mohammadali , Villeneuve Sylvia , Poirier Judes , Breitner John C S , Baillet Sylvain , Bellec Pierre , Bohbot Véronique , Chakravarty Mallar , Collins Louis , Dadar Mahsa , Ducharme Simon , Evans Alan , Geddes Maiya R , Hoge Rick , Multhaup Gerhard , Münter Lisa-Marie , Rajah Natasha , Rosa-Neto Pedro , Soucy Jean-Paul , Spreng Nathan , Tardif Christine , Aumont-Rodrigue Gabriel , Badawy Mohamed , Bailly Julie , Baril Andrée-Ann , Boisvert Lianne , Das Samir , Dauar-Tedeschi Marina , Dery Christine , Élie MarieJosée , Valdez Alfonso Fajardo , Fonov Vladimir , Gallago Jonathan , Greco Claudia , Hudon Louise , Ituria-Medina Yasser , Jean Gabriel , Labonté Anne , Lalancette Marc , Leoutsakos Jeannie-Marie , Mohammediyan Bery , Orban Pierre , Ourry Valentin , Picard Cynthia , Qiu Ting , Quesnel Marc James , Raoult Jean-Michel , Remz Jordana , St-Onge Frederic , Sylvain Elisabeth , Tremblay-Mercier Jennifer , Tullo Stephanie , Vachon-Presseau Etienne , Yakoub Yara , Etienne Pierre , Gauthier Serge , Nair Vasavan , Pruessner Jens , Aisen Paul , Anthal Elena , Appleby Melissa , Ayranci Gülebru , Barkun Alan , Beaudry Thomas , Bedetti Christophe , Benbouhoud Fatiha , Boutin Sophie , Brandt Jason , Carmo Leopoldina , Carrier Charles Edouard , Chapleau Marianne , Cheewakriengkrai Laksanun , Chen Yalin , Courcot Blandine , Couture Doris , Craft Suzanne , Cuello Claudio , Dansereau Christian , Daoust Leslie-Ann , Dea Doris , Debacker Clément , Desautels René , Dubuc Sylvie , Duclair Guerda , Dufour Marianne , Eisenberg Mark , El-Khoury Rana , Farzin Sarah , Faubert Anne-Marie , Ferdinand Fabiola , Fontaine David , Frappier Josée , Frenette Joanne , Gagné Guylaine , Gervais Valérie , Giles Renuka , Gonneaud Julie , Gordon Renee , Jack Clifford R , Kat Justin , Kazazian Christina , Khachaturian Zaven S , Knopman David S , Köbe Theresa , Kostopoulos Penelope , Lafaille-Magnan Marie-Elyse , LeblondBaccichet Gloria , Lee Tanya , Lepage Claude , Leppert Illana , Madjar Cécile , Mahar Laura , Maillet David , Maltais Jean-Robert , Mathieu Axel , Mathotaarachchi Sulantha , Mayrand Ginette , McSweeney Melissa , Meyer Pierre-François , Michaud Diane , Miron Justin , Montine Thomas J , Morris John C , Near Jamie , NewboldFox Holly , Nilsson Nathalie , Ozlen Hazal , Pagé Véronique , Pascoal Tharick A , Peillieux Sandra , Petkova Mirela , Binette Alexa Pichet , Pishnamazi Morteza , Pogossova Galina , Poirier Alexandre , Richer Marie-Josée , Rioux Pierre , Sager Mark A , Saint-Fort Eunice Farah , Salaciak Alyssa , Savard Mélissa , Sperling Reisa A , Strikwerda-Brown Cherie , Tabrizi Shirin , Tam Angela , Tariot Pierre N , Teigner Eduard , Théroux Louise , Thomas Ronald G , Toussaint Paule-Joanne , Tuwaig Miranda , Vallée Isabelle , Venugopalan Vinod , Verfaillie Sander C J , Vogel Jacob , Wan Karen , Wang Seqian , Yu Elsa 
Published: November 2023

Abstract
Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2.
CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada.
CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 [CSF Aβ(+)/t-tau(+)]. In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462).
Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.