Longitudinal pathologic course of older individuals with medial temporal tau deposition in the absence of amyloid‐β pathology

Abstract

AbstractBackgroundAlzheimer’s disease (AD)‐like tau pathology in the medial temporal lobe (MTL) is also commonly observed in older individuals without amyloid‐β (Aβ) pathology, a condition termed primary age‐related tauopathy (PART). Little is known about the longitudinal course of this condition and its association with the AD continuum remains controversial. We used serial PET, MRI, and CSF data to study the longitudinal pathologic course of older individuals who show PET‐measured MTL tau pathology in the absence of Aβ pathology.MethodWe included older individuals with varying degrees of cognitive performance from the Alzheimer’s Disease Neuroimaging Initiative, the Harvard Aging Brain Study, and AVID’s A05 Study who had undergone baseline (n=1097) and follow‐up [18F]flortaucipir (FTP) (n=489, follow‐up: 1.83±0.84 years) and Aβ‐PET scanning (n=398, follow‐up: 2.36±0.76 years). Participants were separated into three groups according to Aβ and tau positivity (A‐T‐, A‐T+, A+T+), using a cut‐off of 12 centiloids for A+ and the 95th percentile of entorhinal (ERC) FTP SUVR values in healthy young controls (n=16, ≤39y) for T+. In complementary analyses we also assessed longitudinal changes in CSF biomarkers (n=99, follow‐up: 2.34±1.05 years) and cortical atrophy on MRI (n=650, follow‐up: 2.00±0.86 years).Result43% of A‐ individuals and 81% of A+ individuals were ERC‐tau positive. Cross‐sectionally, A‐T+ showed elevated FTP SUVR restricted to the medial/inferior temporal lobe, while A+T+ displayed a more AD‐characteristic pattern of widespread cortical FTP uptake (Fig. 1A). A‐T+ showed moderate FTP SUVR increases over time largely limited to the temporal lobe, whereas FTP SUVR increases were widespread in A+T+ (Fig. 1B). Notably, A‐T+ individuals did not increase Aβ accumulation over time (Fig. 1C). CSF analysis confirmed longitudinal tau increases in A‐T+ in the absence of increased Aβ accumulation (Fig. 1D). Compared to A‐T‐, A‐T+ individuals demonstrated accelerated MTL atrophy, whereas A+T+ showed more widespread AD‐typical cortical atrophy (Fig. 2).ConclusionElevated MTL tau‐PET signal is frequently observed in older individuals without notable Aβ pathology, reminiscent of pathology‐defined PART. These A‐T+ individuals exhibit a comparably slow course of progressive tau accumulation and neurodegeneration confined to the temporal lobe and do not appear to be on a pathologic trajectory towards AD.