Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity

Alejandro Costoya‐Sánchez(Universidade de Santiago de Compostela), Alexis Moscoso(University of Gothenburg), Jesús Silva‐Rodríguez(Instituto de Salud Carlos III), Michael J. Pontecorvo(Eli Lilly (United States)), Michael D. Devous(Eli Lilly (United States)), Pablo Aguiar(Universidade de Santiago de Compostela), Michael Schöll(UK Dementia Research Institute), Michel J. Grothe(Instituto de Salud Carlos III), 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 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 C. 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(Alzheimer’s Disease Neuroimaging Initiative), Dorene M. Rentz(Alzheimer’s Disease Neuroimaging Initiative), Rebecca E. Amariglio(Alzheimer’s Disease Neuroimaging Initiative), Deborah Blacker(Alzheimer’s Disease Neuroimaging Initiative), Rachel F. Buckley(Alzheimer’s Disease Neuroimaging Initiative), Jasmeer P. Chhatwal(Alzheimer’s Disease Neuroimaging Initiative), Brad C. Dickerson(Alzheimer’s Disease Neuroimaging Initiative), Nancy J. Donovan(Alzheimer’s Disease Neuroimaging Initiative), Michelle E. Farrell(Alzheimer’s Disease Neuroimaging Initiative), Geoffroy Gagliardi(Alzheimer’s Disease Neuroimaging Initiative), Jennifer R. Gatchel(Alzheimer’s Disease Neuroimaging Initiative), Edmarie Guzmán‐Vélez(Alzheimer’s Disease Neuroimaging Initiative), Heidi I.L. Jacobs(Alzheimer’s Disease Neuroimaging Initiative), Roos J. Jutten(Alzheimer’s Disease Neuroimaging Initiative), Cristina Lois Gómez(Alzheimer’s Disease Neuroimaging Initiative), Gad A. Marshall(Alzheimer’s Disease Neuroimaging Initiative), Kate Oaoo(Alzheimer’s Disease Neuroimaging Initiative), Enmanuelle Pardilla‐Delgado(Alzheimer’s Disease Neuroimaging Initiative), Juliet Price(Alzheimer’s Disease Neuroimaging Initiative), Prokopis C. Prokopiou(Alzheimer’s Disease Neuroimaging Initiative), Yakeel T. Quiroz(Alzheimer’s Disease Neuroimaging Initiative), Gretchen Reynolds(Alzheimer’s Disease Neuroimaging Initiative), Aaron P. Schultz(Alzheimer’s Disease Neuroimaging Initiative), Stephanie A. Schultz(Alzheimer’s Disease Neuroimaging Initiative), Jorge Sepulcre(Alzheimer’s Disease Neuroimaging Initiative), Irina Skylar-Scott(Alzheimer’s Disease Neuroimaging Initiative), Patrizia Vannini(Alzheimer’s Disease Neuroimaging Initiative), Clara Vila‐Castelar(Alzheimer’s Disease Neuroimaging Initiative), Hyun‐Sik Yang(Alzheimer’s Disease Neuroimaging Initiative)
JAMA Neurology
August 14, 2023
10.1001/jamaneurol.2023.2560
Cited by 45Open Access
Full Text

Abstract

Importance: An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear. Objective: To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum. Design, Setting, and Participants: A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-). Exposures: Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments. Main Outcomes and Measures: Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset). Results: Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+. Conclusions and Relevance: In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

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