Age‐related tau‐PET uptake and its downstream effects extend beyond the medial temporal lobe in cognitively normal older adults

Abstract

AbstractBackgroundAmyloid‐beta (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe (MTL). However, there is evidence that age‐related Aβ‐independent tau pathology is present outside the MTL (Kaufman et al., Acta Neuropathol, 2018). We examine tau deposition determined by positron emission tomography (PET) in regions typically involved earlier/later in AD and downstream effects on neurodegeneration and cognition in cognitively unimpaired older adults and a low‐Aβ subgroup.MethodsWe included 488 adults (40‐91 years; low‐Aβ: n=355, 65.2±11.5 years) from the BioFINDER‐2 study. MTL volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex) were obtained, using Automated Segmentation for Hippocampal Subfields packages for T1‐ and T2‐weighted magnetic resonance images. Thickness of early/late neocortical AD‐regions (anterior cingulate, precuneus/posterior cingulate (PPC), orbitofrontal, inferior parietal cortex; and middle frontal, lateral occipital, and precentral/postcentral gyrus) was determined using FreeSurfer. [18F]RO948‐ and [18F]flutemetamol‐PET standardized uptake value ratios (SUVRs) were calculated for local tau and global/local Aβ. Aβ status was determined using Aβ‐PET or cerebrospinal fluid Aβ‐42/40 ratio. Global cognition was measured using delayed word‐list recall, trail making test B, and animal fluency.ResultsIncreasing age was associated with higher tau‐PET SUVRs primarily in MTL/frontal/parietal regions. A significant association between age and local tau‐PET remained even when including Aβ‐PET as a mediator (Fig. 1).Age and local tau‐PET, but not Aβ‐PET, where negatively associated with structure in most examined regions (Figs. 2‐3). Age‐structure associations were serially mediated via tau‐PET in regions with early AD pathology (SUB/BA35/PPC). Also, in the low‐Aβ subgroup, tau‐PET mediated the age‐structure (SUB/BA35/PPC) associations (Fig. 3D). Finally, the age‐global cognition relationship was serially mediated via MTL tau‐PET and subiculum volume, even when including global Aβ‐PET as additional mediator (Fig. 4).ConclusionWe observe partially Aβ‐independent associations between age and tau‐PET signal across the neocortex. Interestingly, partially Aβ‐independent tau‐PET signal appears to mediate the age‐structure associations in and outside the MTL (PPC), also in the low‐Aβ group, and the age‐MTL structure‐cognition associations. This potentially provides in vivo support for Primary Age‐related Tauopathy downstream effects on structure, beyond the MTL, and cognition.