Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease

Christina B. Young(Stanford University), Joseph R. Winer(Stanford University), Kyan Younes(Stanford University), Karly Alex Cody(University of Wisconsin–Madison), Tobey J. Betthauser(University of Wisconsin–Madison), Sterling C. Johnson(University of Wisconsin–Madison), Aaron P. Schultz(Harvard University), Reisa A. Sperling(Brigham and Women's Hospital), Michael D. Greicius(Stanford University), Inma Cobos(Stanford University), Kathleen L. Poston(Stanford University), Elizabeth C. Mormino(Stanford University), Alzheimer’s Disease Neuroimaging Initiative and the Harvard Aging Brain Study(Alzheimer’s Disease Neuroimaging Initiative), Michael W. Weiner(Alzheimer’s Disease Neuroimaging Initiative), Paul Aisen(Alzheimer’s Disease Neuroimaging Initiative), Ronald C. Petersen(Alzheimer’s Disease Neuroimaging Initiative), Clifford R. Jack(Alzheimer’s Disease Neuroimaging Initiative), William J. Jagust(Alzheimer’s Disease Neuroimaging Initiative), John Q. Trojanowki(Alzheimer’s Disease Neuroimaging Initiative), Arthur W. Toga(Alzheimer’s Disease Neuroimaging Initiative), Laurel Beckett(Alzheimer’s Disease Neuroimaging Initiative), Robert C. Green(Alzheimer’s Disease Neuroimaging Initiative), Andrew J. Saykin(Alzheimer’s Disease Neuroimaging Initiative), John C. Morris(Alzheimer’s Disease Neuroimaging Initiative), Richard J. Perrin(Alzheimer’s Disease Neuroimaging Initiative), Leslie M. Shaw(Alzheimer’s Disease Neuroimaging Initiative), Zaven S. Khachaturian(Alzheimer’s Disease Neuroimaging Initiative), María C. Carrillo(Alzheimer’s Disease Neuroimaging Initiative), William Z. Potter(Alzheimer’s Disease Neuroimaging Initiative), Lisa L. Barnes(Alzheimer’s Disease Neuroimaging Initiative), Marie Bernard(Alzheimer’s Disease Neuroimaging Initiative), Héctor Alfredo Baptista González(Alzheimer’s Disease Neuroimaging Initiative), Carole Ho(Alzheimer’s Disease Neuroimaging Initiative), John Hsiao(Alzheimer’s Disease Neuroimaging Initiative), Jonathan Jackson(Alzheimer’s Disease Neuroimaging Initiative), Eliezer Masliah(Alzheimer’s Disease Neuroimaging Initiative), Donna Masterman(Alzheimer’s Disease Neuroimaging Initiative), Ozioma C. Okonkwo(Alzheimer’s Disease Neuroimaging Initiative), Laurie Ryan(Alzheimer’s Disease Neuroimaging Initiative), Nina Silverberg(Alzheimer’s Disease Neuroimaging Initiative), Adam Fleisher(Alzheimer’s Disease Neuroimaging Initiative), Diana Truran Sacrey(Alzheimer’s Disease Neuroimaging Initiative), Juliet Fockler(Alzheimer’s Disease Neuroimaging Initiative), Cat Conti(Alzheimer’s Disease Neuroimaging Initiative), Dallas P. Veitch(Alzheimer’s Disease Neuroimaging Initiative), John Neuhaus(Alzheimer’s Disease Neuroimaging Initiative), Chengshi Jin(Alzheimer’s Disease Neuroimaging Initiative), Rachel L. Nosheny(Alzheimer’s Disease Neuroimaging Initiative), Mariam Ashford(Alzheimer’s Disease Neuroimaging Initiative), Derek Flenniken(Alzheimer’s Disease Neuroimaging Initiative), Adrienne Kormos(Alzheimer’s Disease Neuroimaging Initiative), Tom Montine(Alzheimer’s Disease Neuroimaging Initiative), Michael S. Rafii(Alzheimer’s Disease Neuroimaging Initiative), Rema Raman(Alzheimer’s Disease Neuroimaging Initiative), Gustavo Jiménez(Alzheimer’s Disease Neuroimaging Initiative), Michael Donohue(Alzheimer’s Disease Neuroimaging Initiative), Devon Gessert(Alzheimer’s Disease Neuroimaging Initiative), Jennifer Salazar(Alzheimer’s Disease Neuroimaging Initiative), Caileigh Zimmerman(Alzheimer’s Disease Neuroimaging Initiative), Yuliana Cabrera(Alzheimer’s Disease Neuroimaging Initiative), Sarah Walter(Alzheimer’s Disease Neuroimaging Initiative), Garrett Miller(Alzheimer’s Disease Neuroimaging Initiative), Godfrey Coker(Alzheimer’s Disease Neuroimaging Initiative), Taylor Clanton(Alzheimer’s Disease Neuroimaging Initiative), Lindsey Hergesheimer(Alzheimer’s Disease Neuroimaging Initiative), Stephanie Smith(Alzheimer’s Disease Neuroimaging Initiative), Olusegun Adegoke(Alzheimer’s Disease Neuroimaging Initiative), Payam Mahboubi(Alzheimer’s Disease Neuroimaging Initiative), Shelley Moore(Alzheimer’s Disease Neuroimaging Initiative), Jeremy Pizzola(Alzheimer’s Disease Neuroimaging Initiative), Elizabeth Shaffer(Alzheimer’s Disease Neuroimaging Initiative), Danielle Harvey(Alzheimer’s Disease Neuroimaging Initiative), Arvin Forghanian-Arani(Alzheimer’s Disease Neuroimaging Initiative), Bret Borowski(Alzheimer’s Disease Neuroimaging Initiative), Chad Ward(Alzheimer’s Disease Neuroimaging Initiative), Christopher G. Schwarz(Alzheimer’s Disease Neuroimaging Initiative), David T. Jones(Alzheimer’s Disease Neuroimaging Initiative), Jeff Gunter(Alzheimer’s Disease Neuroimaging Initiative), Kejal Kantarci(Alzheimer’s Disease Neuroimaging Initiative), Matthew L. Senjem(Alzheimer’s Disease Neuroimaging Initiative), Prashanthi Vemuri(Alzheimer’s Disease Neuroimaging Initiative), Robert I. Reid(Alzheimer’s Disease Neuroimaging Initiative), Nick C. Fox(Alzheimer’s Disease Neuroimaging Initiative), Ian B. Malone(Alzheimer’s Disease Neuroimaging Initiative), Paul M. Thompson(Alzheimer’s Disease Neuroimaging Initiative), Sophia I. Thomopoulos(Alzheimer’s Disease Neuroimaging Initiative), Talia M. Nir(Alzheimer’s Disease Neuroimaging Initiative), Neda Jahanshad(Alzheimer’s Disease Neuroimaging Initiative), Charles DeCarli(Alzheimer’s Disease Neuroimaging Initiative), Alexander Knaack(Alzheimer’s Disease Neuroimaging Initiative), Evan Fletcher(Alzheimer’s Disease Neuroimaging Initiative), Duygu Tosun(Alzheimer’s Disease Neuroimaging Initiative), Stephanie R Chen(Alzheimer’s Disease Neuroimaging Initiative), Mark Choe(Alzheimer’s Disease Neuroimaging Initiative), Karen Crawford(Alzheimer’s Disease Neuroimaging Initiative), Paul A Yuschkevich(Alzheimer’s Disease Neuroimaging Initiative), Sandhitsu R. Das(Alzheimer’s Disease Neuroimaging Initiative), Robert A. Koeppe(Alzheimer’s Disease Neuroimaging Initiative), Eric M. Reiman(Alzheimer’s Disease Neuroimaging Initiative), Kewei Chen(Alzheimer’s Disease Neuroimaging Initiative), Chet Mathis(Alzheimer’s Disease Neuroimaging Initiative), Susan Landau(Alzheimer’s Disease Neuroimaging Initiative), Nigel J. Cairns(Alzheimer’s Disease Neuroimaging Initiative), Erin Householder(Alzheimer’s Disease Neuroimaging Initiative), Erin Franklin(Alzheimer’s Disease Neuroimaging Initiative), Haley Bernhardt(Alzheimer’s Disease Neuroimaging Initiative), Lisa Taylor‐Reinwald(Alzheimer’s Disease Neuroimaging Initiative), Magdalena Korecka(Alzheimer’s Disease Neuroimaging Initiative), Michal Figurski(Alzheimer’s Disease Neuroimaging Initiative), Scott Neu(Alzheimer’s Disease Neuroimaging Initiative), Kwangsik Nho(Alzheimer’s Disease Neuroimaging Initiative), Shannon L. Risacher(Alzheimer’s Disease Neuroimaging Initiative), Liana G. Apostolova(Alzheimer’s Disease Neuroimaging Initiative), Li Shen(Alzheimer’s Disease Neuroimaging Initiative), Tatiana Foroud(Alzheimer’s Disease Neuroimaging Initiative), Kelly Nudelman(Alzheimer’s Disease Neuroimaging Initiative), Kelley Faber(Alzheimer’s Disease Neuroimaging Initiative), Kristi Wilmes(Alzheimer’s Disease Neuroimaging Initiative), Leon J. Thal(Alzheimer’s Disease Neuroimaging Initiative), Keith A. Johnson(Alzheimer’s Disease Neuroimaging Initiative), Reisa A. Sperling(Brigham and Women's Hospital)
JAMA Neurology
April 18, 2022
10.1001/jamaneurol.2022.0676
Cited by 77Open Access
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Abstract

Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease. Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+). Design, Setting, and Participants: This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022. Main Outcomes and Measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined. Results: The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin. Conclusions and Relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

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