Association of Elevated Amyloid and Tau Positron Emission Tomography Signal With Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment
Cherie Strikwerda‐Brown, Diana A. Hobbs, Julie Gonneaud, Frédéric St‐Onge, Alexa Pichet Binette, Hazal Ozlen, Karine Provost, Jean‐Paul Soucy, Rachel F. Buckley, Tammie L.S. Benzinger, John C. Morris, Victor L. Villemagne, Vincent Doré, Reisa A. Sperling, Keith A. Johnson, Christopher C. Rowe, Brian A. Gordon, Judes Poirier, John C.S. Breitner, Sylvia Villeneuve, Angela Tam, Anne Labonté, Alexa Pichet Binette, Anne‐Marie Faubert, Axel Mathieu, Cécile Madjar, Charles Edouard Carrier, Christian Dansereau, Christina Kazazian, Claude Lepage, Cynthia Picard, David Maillet, Diane Michaud, Doris Couture, Doris Dea, A. Claudio Cuello, Alan Barkun, Alan C. Evans, Blandine Courcot, Christine Tardif, Clément Debacker, Clifford R. Jack, David Fontaine, David S. Knopman, Gerhard Multhaup, Jamie Near, Jeannie‐Marie Leoutsakos, Jean‐Robert Maltais, Jason Brandt, Jens C. Pruessner, John C. Morris, John C.S. Breitner, Judes Poirier, Laksanun Cheewakriengkrai, Lisa-Marie MÃ ⁄ nter, D. Louis Collins, M. Mallar Chakravarty, Mark A. Sager, Marina Dauar‐Tedeschi, Mark J. Eisenberg, Natasha Rajah, Paul Aisen, Paule‐Joanne Toussaint, Pedro Rosa‐Neto, Pierre Bellec, Penelope Kostopoulos, Pierre Étienne, Pierre N. Tariot, Pierre Orban, Reisa A. Sperling, Rick Hoge, Ronald G. Thomas, Serge Gauthier, Suzanne Craft, Sylvia Villeneuve, Thomas J. Montine, Vasavan Nair, Véronique D. Bohbot, Vinod Venugopalan, Vladimir Fonov, Yasser Ituria‐Medina, Zaven S. Khachaturian, Eduard Teigner, Elena Anthal, Elsa Yu, Fabiola Ferdinand, Galina Pogossova, Ginette Mayrand, Guerda Duclair, Guylaine Gagné, Holly Newbold‐Fox, Illana Leppert, Isabelle Vallée, Jacob W. Vogel, Jennifer Tremblay‐Mercier, Joanne Frenette, Josée Frappier, Justin Kat, Justin Miron, Karen Wan
Abstract
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.