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

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.