Association of Elevated Amyloid and Tau Positron Emission Tomography Signal With Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment
Authors: Strikwerda-Brown Cherie , Hobbs Diana A. , Gonneaud Julie , St-Onge Frédéric , Binette Alexa Pichet , Ozlen Hazal , Provost Karine , Soucy Jean-Paul , Buckley Rachel F. , Benzinger Tammie L. S. , Morris John C. , Villemagne Victor L. , Doré Vincent , Sperling Reisa A. , Johnson Keith A. , Rowe Christopher C. , Gordon Brian A. , Poirier Judes , Breitner John C. S. , Villeneuve Sylvia ,   PREVENT-AD, HABS, and AIBL Research Groups, 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 , 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 , Masters Colin L , Ward Larry , Maruff Paul , Fowler Christopher , Martins Ralph , Rainy-Smith Stephanie , Taddei Kevin , Brown Belinda , Laws Simon , Fripp Jurgen , Bourgeat Pierrick 
Published: July 2022

Importance

National Institute on Aging–Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD).

Objective

To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD.

Design, Setting, and Participants

This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years.

Exposures

Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T−, A−T+, A−T−). Presence (+) or absence (−) of neurodegeneration (N) was assessed using temporal cortical thickness.

Main Outcomes and Measures

Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups.

Results

Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable.

Conclusions and Relevance

The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.