Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity
Authors: Costoya-Sánchez Alejandro , Moscoso Alexis , Silva-Rodríguez Jesús , Pontecorvo Michael J. , Devous Michael D. , Aguiar Pablo , Schöll Michael , Grothe Michel J. ,   Alzheimer’s Disease Neuroimaging Initiative and the Harvard Aging Brain Study, Weiner Michael W , Aisen Paul , Petersen Ronald , Jack Clifford R , Jagust William , Trojanowki John Q , Toga Arthur W , Beckett Laurel , Green Robert C , Saykin Andrew J , Morris John C , Perrin Richard J , Shaw Leslie M , Khachaturian Zaven , Carrillo Maria , Potter William , Barnes Lisa , Bernard Marie , Gonzalez Hector , Ho Carole , Hsiao John K , Jackson Jonathan , Masliah Eliezer , Masterman Donna , Okonkwo Ozioma , Ryan Laurie , Silverberg Nina , Fleisher Adam , Sacrey Diana T , Fockler Juliet , Conti Cat , Veitch Dallas , Neuhaus John , Jin Chengshi , Nosheny Rachel , Ashford Mariam , Flenniken Derek , Kormos Adrienne , Montine Tom , Rafii Michael , Raman Rema , Jimenez Gustavo , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Cabrera Yuliana , Walter Sarah , Miller Garrett , Coker Godfrey , Clanton Taylor , Hergesheimer Lindsey , Smith Stephanie , Adegoke Olusegun , Mahboubi Payam , Moore Shelley , Pizzola Jeremy , Shaffer Elizabeth , Harvey Danielle , Forghanian-Arani Arvin , Borowski Bret , Ward Chad , Schwarz Christopher , Jones David , Gunter Jeff , Kantarci Kejal , Senjem Matthew , Vemuri Prashanthi , Reid Robert , Fox Nick C , Malone Ian , Thompson Paul , Thomopoulos Sophia I , Nir Talia M , Jahanshad Neda , DeCarli Charles , Knaack Alexander , Fletcher Evan , Tosun-Turgut Duygu , Chen Stephanie R , Choe Mark , Crawford Karen , Yuschkevich Paul A , Das Sandhitsu , Koeppe Robert A , Reiman Eric M , Chen Kewei , Mathis Chet , Landau Susan , Cairns Nigel J , Householder Erin , Franklin Erin , Bernhardt Haley , Taylor-Reinwald Lisa , Korecka Magdalena , Figurski Michal , Neu Scott , Nho Kwangsik , Risacher Shannon L , Apostolova Liana G , Shen Li , Foroud Tatiana M , Nudelman Kelly , Faber Kelley , Wilmes Kristi , Thal Leon , Johnson Keith A , Sperling Reisa A , Rentz Dorene , E. Amariglio Rebecca , 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 Juliet , Prokopiou Prokopis , Quiroz Yakeel , Reynolds Gretchen , Schultz Aaron , Schultz Stephanie , Sepulcre Jorge , Skylar-Scott Irina , Vannini Patrizia , Vila-Castelar Clara , Yang Hyun-Sik 
Published: August 2023

ImportanceAn 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.ObjectiveTo 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 ParticipantsA 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−).ExposuresTau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments.Main Outcomes and MeasuresCross-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).ResultsAmong 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 &amp;lt;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 RelevanceIn 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.