Evidence for the progression of tau and neurodegeneration beyond the medial temporal lobe in amyloid-negative older adults.

Abstract

Despite the important role of tau in Alzheimer's disease (AD), tau in the absence of amyloid (Aβ) is typically considered as separable from the AD continuum. Our previous research demonstrated a high proportion of elevated tau PET (Braak stage I/II) in the context of normal Aβ PET, and that this group exhibited subtle cognitive deficits. Here we extend these findings to investigate whether there also exists a subset of amyloid negative individuals who have progressed in their tauopathy to Braak stage III/IV. A sample of 467 older adults across the AD clinical spectrum from the Alzheimer's Disease Neuroimaging Initiative who had concurrent Aβ and tau PET data were included. Participants were categorized as positive or negative for cortical Aβ (A) and tau Braak stage III/IV (T34) PET and fell into one of four groups: A-/T34-, A+/T34-, A-/T34+, A+/T34+. Resultant groups were compared on demographic factors, apolipoprotein E (APOE) genetic risk, vascular risk (i.e., pulse pressure), and volume/cortical thickness (n = 300) of the hippocampus, inferior temporal gyrus, and inferior parietal lobe. The following proportions were observed: 54% A-/T34-, 19% A+/T34-, 5% A-/T34+, and 22% A+/T34+. Specifically, 23 individuals had elevated Braak III/IV tau PET in the absence of cortical Ab. This A-/T34+ group did not differ from other groups in age, sex, or pulse pressure, but did have a lower proportion of APOE ε4 carriers. Further, the A-/T34+ group did not differ from the A+/T34+ group on any measures of volume/cortical thickness but had lower volume/thickness than both T34- groups. These findings suggest that tau pathology can extend beyond the medial temporal lobe in the continued absence of Aβ and exert the same degree of neurodegenerative effects as if Aβ were present. Regardless of the classification of these individuals in relation to current definitional nosologies for AD (see Jack et al. 2020), tau appears capable of progressing through Braak stages I-IV in a malignant manner independent of Aβ, exerting similar neurodegenerative effects observed as one advances along the AD continuum. Results highlight the need to target tau-only individuals in clinical treatment trials and the deleterious consequences of excluding such individuals.