Spatial Extent of Amyloid-β Levels and Associations With Tau-PET and Cognition
Authors: Ozlen Hazal , Pichet Binette Alexa , Köbe Theresa , Meyer Pierre-François , Gonneaud Julie , St-Onge Frédéric , Provost Karine , Soucy Jean-Paul , Rosa-Neto Pedro , Breitner John , Poirier Judes , Villeneuve Sylvia ,   Alzheimer’s Disease Neuroimaging Initiative, the Harvard Aging Brain Study, the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease Research Group, Tam Angela , Labonte Anne , Pichet Binette Alexa , Faubert Anne-Marie , Mathieu Axel , Madjar Cecile , Carrier Charles Edouard , Dansereau Christian , Kazazian Christina , Lepage Claude , Picard Cynthia , Maillet David , Michaud Diane , Couture Doris , Dea Doris , Cuello Claudio , Barkun Alan , Evans Alan , Courcot Blandine , Tardif Christine , Debacker Clement , Jack Clifford , Fontaine David , Knopman David , Multhaup Gerhard , Near Jamie , Leoutsakos Jeannie-Marie , Maltais Jean-Robert , Brandt Jason , Pruessner Jens , Morris John , Breitner John , Poirier Judes , Cheewakriengkrai Laksanun , MÃ¼nter Lisa-Marie , Collins Louis , Chakravarty Mallar , Sager Mark , Dauar-Tedeschi Marina , Eisenberg Mark , Rajah Natasha , Aisen Paul , Toussaint Paule-Joanne , Rosa-Neto Pedro , Bellec Pierre , Kostopoulos Penelope , Etienne Pierre , Tariot Pierre , Orban Pierre , Sperling Reisa , Hoge Rick , Thomas Ronald , Gauthier Serge , Craft Suzanne , Villeneuve Sylvia , Montine Thomas , Nair Vasavan , Bohbot Veronique , Venugopalan Vinod , Fonov Vladimir , Ituria-Medina Yasser , Khachaturian Zaven , Teigner Eduard , Anthal Elena , Yu Elsa , Ferdinand Fabiola , Pogossova Galina , Mayrand Ginette , Duclair Guerda , Gagne Guylaine , Newbold-Fox Holly , Leppert Illana , Vallee Isabelle , Vogel Jacob , Tremblay-Mercier Jennifer , Frenette Joanne , Frappier Josee , Kat Justin , Miron Justin , Wan Karen , Mahar Laura , Carmo Leopoldina , Theroux Louise , Dadar Mahsa , Dufour Marianne , Lafaille-Magnan Marie-Elyse , Appleby Melissa , Savard Melissa , Tuwaig Miranda , Petkova Mirela , Rioux Pierre , Meyer Pierre-FranÃ§ois , El-Khoury Rana , Gordon Renee , Giles Renuka , Das Samir , Wang Seqian , Tabrizi Shirin , Mathotaarachchi Sulantha , Dubuc Sylvie , Lee Tanya , Beaudry Thomas , Gervais Valerie , Page Veronique , Gonneaud Julie , Ayranci GÃ¼lebru , Pascoal Tharick , Desautels Rene , Benbouhoud Fatiha , Saint-Fort Eunice Farah , Verfaillie Sander , Farzin Sarah , Salaciak Alyssa , Tullo Stephanie , Vachon-Presseau Etienne , Daoust Leslie-Ann , Kobe Theresa , Spreng Nathan , McSweeney Melissa , Nilsson Nathalie , Pishnamazi Morteza , Bedetti Christophe , Hudon Louise , Greco Claudia , Chapleau Marianne , St-Onge Frederic , Boutin Sophie , Geddes Maiya , Ducharme Simon , Jean Gabriel , Sylvain Elisabeth , Ã‰lie Marie-Josee , Leblond-Baccichet Gloria , Soucy Jean-Paul , Ozlen Hazal , Bailly Julie , Mohammediyan Bery , Chen Yalin , Remz Jordana , Weiner Michael W , Peterson 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 , Carrillo Maria , Porter William , Barnes Lisa , Bernard Marie , Gonzalez Hector , Ho Carole , Hsiao John K , Jackson Jonathan , Masliah Eliezer , Masterman Donna , Okonkwo Ozioma , Ryan Laurie , Silverberg Nina , Fleisher Adam , Truran Sacrey Diana , Fockler Juliet , Conti Cat , Veitch Dallas , Neuhaus John , Jin Chengshi , Nosheny Rachel , Ashford Miriam , Flenniken Derek , Kormos Adrieene , Montine Tom , Rafii Micheal , Raman Rema , Jimenez Gustavo , Donohue Micheael , 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 , Harvey Danielle , Forghanian-Arani Arivn , Borowski Bret , Ward Chad , Schwarz Christopher , Jones David , Gunter Jeff , Kantarci Kejal , Senjen Matthew , Vermuri Prashanthi , Reid Robert C , Fox Nick C , Malone Ian , Thompson Paul , Tohomopoulous Sophia I , Nir Talia M. , Jahanshad Neda , DeCarli Charles , Knaack Alexander , Fletcher Evan , Tosun-Turgut Duygu , Rossi Chen Stephanie , Choe Mark , Crawford Karen , Yushkevich Paul A. , Das Sandhitsu , Koeppe Robert A. , Reiman Eric M. , Chen Kewei , Mathis Chet , Landau Susan , Morris John C. , Perrin Richard , Cairns Nigel J. , Householder Erin , Franklin Erin , Bernhardt Haley , Taylor-Reinwald Lisa , Korecka Magdalena , Figurski Michal , Neu Scott , Nho Kwangski , Risacher Shannon , Apostolova Liana G , Shen Li , Foroud Tatiana M , Nudelman Kelly , Faber Kelley , Wilmes Kristi , Thal Leon , Johnson Keith , Rentz Dorene , Amariglio Rebecca E. , Blacker Deborah , Buckley Rachel , Chhatwal Jasmeer P. , Dickerson Brad , Donovan Nancy , Farrell Michelle , Gagliardi Geoffroy , Gatchel Jennifer , Guzman-Velez Edmarie , Jacobs Heidi , Jutten Roos , Lois Gomez Cristina , Marshall Gad , Oaoo Kate , Pardilla-Delgado Enmanuelle , Price Julie , Prokopiou Prokopis , Quiroz Yakeel , Reynolds Gretchen , Schultz Aaron , Schultz Stephanie , Sepulcre Jorge , Skylar-Scott Irina , Vannini Patrizia , Vila-Castelar Clara , Yang Hyun-Sik 
Published: August 2022

Importance

Preventive trials of anti-amyloid agents might preferably recruit persons showing earliest biologically relevant β-amyloid (Aβ) binding on positron emission tomography (PET).

Objective

To investigate the timing at which Aβ-PET binding starts showing associations with other markers of Alzheimer disease.

Design, Setting, and Participants

This longitudinal multicentric cohort study included 3 independent cohorts: Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) (data collected from 2012-2020), Alzheimer Disease Neuroimaging Initiative (ADNI) (data collected from 2005-2019), and Harvard Aging Brain Study (HABS) (data collected from 2011-2019). In a 3-tiered categorization of Aβ-PET binding spatial extent, individuals were assigned as having widespread Aβ deposition if they showed positive signal throughout a designated set of brain regions prone to early Aβ accumulation. Those with binding in some but not all were categorized as having regional deposition, while those who failed to show any criterion Aβ signal were considered Aβ-negative. All participants who were cognitively unimpaired at their first Aβ PET scan.

Main Outcomes and Measures

Differences in cerebrospinal fluid (CSF), genetics, tau-PET burden, and cognitive decline.

Results

A total of 817 participants were included, including 129 from the PREVENT-AD cohort (mean [SD] age, 63.5 [4.7] years; 33 [26%] male; 126 [98%] White), 400 from ADNI (mean [SD] age, 73.6 [5.8] years; 190 [47%] male; 10 [5%] Hispanic, 338 [91%] White), and 288 from HABS (mean [SD] age, 73.7 [6.2] years; 117 [40%] male; 234 [81%] White). Compared with Aβ-negative persons, those with regional Aβ binding showed proportionately more APOE ε4 carriers (18 [64%] vs 22 [27%] in PREVENT-AD and 34 [31%] vs 38 [19%] in ADNI), reduced CSF Aβ1-42 levels (F = 24 and 71), and greater longitudinal Aβ-PET accumulation (significant β = 0.019 to 0.056). Participants with widespread amyloid binding further exhibited notable cognitive decline (significant β = −0.014 to −0.08), greater CSF phosphorylated tau181 (F = 5 and 27), and tau-PET binding (all F &amp;gt; 7.55). Using each cohort’s specified dichotomous threshold for Aβ positivity or a visual read classification, most participants (56% to 100%, depending on classification method and cohort) with regional Aβ would have been classified Aβ-negative.

Conclusions and Relevance

Regional Aβ binding appears to be biologically relevant and participants at this stage remain relatively free from CSF phosphorylated tau181, tau-PET binding, and related cognitive decline, making them ideal targets for anti-amyloid agents. Most of these individuals would be classified as negative based on classical thresholds of Aβ positivity.