Evaluation of the Revised Criteria for Biological and Clinical Staging of Alzheimer Disease
Authors: Alexa Pichet Binette, Ruben Smith, Gemma Salvadó, Pontus Tideman, Isabelle Glans, Danielle van Westen, Colin Groot, Rik Ossenkoppele, Erik Stomrud, Piero Parchi, Henrik Zetterberg, Kaj Blennow, Niklas Mattsson-Carlgren, Shorena Janelidze, Sebastian Palmqvist, Oskar Hansson, Olusegun Adegoke, Kedir Adem Hussen, Paul Aisen, Adeyinka Ajayi, Hannatu Amaza, Liana G. Apostolova, Miriam Ashford, Omobolanle Ayo, Lisa Barnes, Laurel Beckett, Marie Bernard, Haley Bernhardt, Virginia Boatwright, Bret Borowski, Magdalena Brylska, Neil Buckholtz, Yuliana Cabrera, Nigel J. Cairns, Maria Carrillo, Mark Choe, Taylor Clanton, Cat Conti, Hannah Craft, Karen Crawford, Sandhitsu Das, Charles DeCarli, Joseph Di Benedetto, Adam Diaz, Michael Donohue, Erin Drake, Claire Erickson, Kelley Faber, Joel Felmlee, Andrea Fidell, Derek Flenniken, Evan Fletcher, Juliet Fockler, Arvin Forghanian-Arani, Tatiana M. Foroud, Nick C. Fox, Richard Frank, Erin Franklin, Matt Glittenberg, Hector González, Robert C. Green, Joshua Grill, Jeff Gunter, Vanessa Guzman, Kristin Harkins, Danielle Harvey, Caitie Hedberg, Lindsey Hergesheimer, Carole Ho, Isabella Hoang, John K. Hsiao, Clifford R. Jack, Jonathan Jackson, William Jagust, Neda Jahanshad, Cecily Jenkins, Gustavo Jimenez, Chengshi Jin, Taeho Jo, Zaven Kachaturian, Rima Kaddurah-Daouk, Kejal Kantarci, Jason Karlawish, Zaven Khachaturian, Alexander Knaack, Robert A. Koeppe, Magdalena Korecka, Adrienne Kormos, Kaori Kubo Germano, Winnie Kwang, Kaci Lacy, Susan Landau, Emily Largent, Edward B. Lee, Virginia M.Y. Lee, Brian LoPresti, Fabiola Magana, Payam Mahboubi, Ian Malone, Eliezer Masliah, Donna Masterman, Leonard Matoush, Melanie J. Miller, Susan Molchan, Tom Montine, John Moore-Weiss, John Morris, Scott Neu, Kwangsik Nho, Talia M. Nir, Rachel Nosheny, Kelly Nudelman, Sheila Ogwang, Ozioma Okonkwo, Shaniya Parkins, Richard Perrin, Ronald Petersen, Jeremy Pizzola, Zoë Potter, William Potter, Gil Rabinovici, Michael Rafii, Rema Raman, Robert Reid, Calvin Reyes, Denise Reyes, Shannon L. Risacher, Monica Rivera-Mindt, Justin Robison, Stephanie Rossi Chen, Laurie Ryan, Pallavi Sachdev, Naomi Saito, Jennifer Salazar, Andrew J. Saykin, Christopher Schwarz, Mai Seng Thao, Matthew Senjem, Elizabeth Shaffer, Leslie M. Shaw, Li Shen, Nina Silverberg, Stephanie Smith, Peter J. Snyder, Joe Strong, Sandra Talavera, Lisa Taylor-Reinwald, Leon Thal, Lisa Thomas, Sophia I. Thomopoulos, Paul Thompson, Arthur W. Toga, Duygu Tosun, J.Q. Trojanowki, Diana Truran Sacrey, Prashanthi Vemuri, Victor Villemagne, Sarah Walter, Yang Wan, Chad Ward, Caitlin Webb, Michael Weiner, Trinity Weisensel, Paul A. Yushkevich, Caileigh Zimmerman
Journal: JAMA Neurology (2025)

Importance While clinical disease stages remained largely unchanged in the 2024 update of the Alzheimer disease (AD) criteria, tau–positron emission tomography (PET) was introduced as a core biomarker and its spatial extent was incorporated into the revised biological stages of the disease. It is important to consider both the clinical and the biological stages and understand their discrepancies. Objective To compare individuals who have discrepant biological and clinical stages with those who have congruent stages in terms of copathologies, comorbidities, and demographics. Design, Setting, and Participants Participants were from the Swedish BioFINDER-2 (inclusion from 2017 through 2023) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (inclusion from 2015 through 2024). BioFINDER-2 included a prospective population-based (cognitively normal [CN] older adults) and memory clinic–based cohort (participants with subjective cognitive impairment [SCD], mild cognitive impairment [MCI], and dementia). ADNI included a volunteer-based sample. All participants who were amyloid-β positive and had undergone tau-PET were included. In BioFINDER-2, 838 participants of a total of 1979 were included, and of 927 with tau-PET in ADNI, 380 were included. Exposures The clinical (CN to dementia) and biological (based on PET; initial [amyloid-β-positive only] to advanced [amyloid-β-positive, elevated, and widespread tau]) stages from the revised AD criteria. Main Outcomes and Measures Cross-sectional measures of neurodegeneration (cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature, neurofilament light [NfL]), α-synuclein cerebrospinal fluid status, plasma glial fibrillary acidic protein, white matter lesions, infarcts, microbleeds, comorbidities, and demographics. Results There were 838 BioFINDER-2 participants (mean age, 73.9 [SD, 7.3] years; 431 women [51%]; 407 men [49%]) and 380 ADNI participants (average age, 72.9 [SD, 7.0] years; 194 women [51%]; 186 mean [49%]) included. In BioFINDER-2, 37.7% of the sample had congruent biological and clinical stages (reference group), 51.3% had more advanced clinical impairment compared with their clinical stage (clinical &amp;amp;gt; biological) and 11.0% had the opposite (biological &amp;amp;gt; clinical). The main differences were between the reference group and the clinical &amp;amp;gt; biological group: the latter participants were more often positive for α-synuclein pathology, had higher NfL levels, greater TDP-43–like atrophy, and higher burden of cerebral small vessel disease lesions (all false discovery rate P &amp;amp;lt; .05). The only difference between the biological &amp;amp;gt; clinical and the reference group was that the former had less neurodegeneration (thicker cortex; all false discovery rate P &amp;amp;lt; .001). The main results were replicated in the independent ADNI cohort, where congruent 56.1% of participants had biological and clinical stages; 36.1% were in the category clinical &amp;amp;gt; biological, and 7.9% in biological &amp;amp;gt; clinical. Conclusions and Relevance Copathologies play an important role in symptom severity in individuals who harbor less tau-tangle pathology than expected for their clinical impairment. These results highlight the importance of measuring non–AD biomarkers in patients with AD with worse cognitive impairment than expected based on their biological stage, which could impact the clinical diagnosis and prognosis.