Pathological tau in cognitively normal older adults predicts prospective neurodegeneration and cognitive decline

Abstract

BackgroundPathological tau burden has been linked to neurodegeneration in AD patients. Although previous studies have linked brain atrophy in people at the preclinical stage of AD to early tau deposition, most evidence is based on cross‐sectional findings or retrospective changes before the tau measurement. This study examines longitudinal atrophy and cognitive decline following the assessment of tau, and specifically the relationship between whole brain tau measures and prospective changes in brain structure and memory.Methods124 cognitively normal older adults (> 65 yrs old) underwent FTP PET to measure voxel‐wise tau pathology and PiB PET to measure amyloid positivity at baseline. Rates of change in hippocampal volume (N=74) and memory (N=108) following the PET scan were correlated with whole brain (voxel‐wise) FTP‐PET data.ResultsProspective memory decline was related to tau deposition in the left temporal, parietal, and posterior regions, and the right parahippocampal gyrus (Figure 1), driven by Aß+ individuals (Figure 2). Prospective hippocampal atrophy was related to tau in the parahippocampal and entorhinal cortices (Figure 3), regardless of Aß status. The overlapping cluster in the right parahippocampal/entorhinal region suggested tau burden in this area was predictive of both hippocampal atrophy and memory decline (Figure 4). Finally, we explored how tau and hippocampal atrophy contributed to memory decline together. We found that memory decline in Aß‐ people was mediated by hippocampal atrophy (31.9%) and that there was very little direct effect of tau on memory decline. However, no mediation of hippocampal atrophy was found in Aß+ people, suggesting a strong effect of tau on memory decline in Aß+ people above and beyond hippocampal atrophy (Figure 5).ConclusionsOur findings suggest that tau effects on cognitive decline and neurodegeneration are already present in cognitively normal people, and that memory decline may be driven by different factors in normal aging and preclinical AD. Entorhinal tau in Aß‐ adults may be linked to age‐related hippocampal atrophy, which was related to memory decline, whereas degeneration in other regions, or other brain changes (e.g., network integrity, functional activity, etc.), may explain the detrimental effect of tau on memory in Aß+ people.