Longitudinal tau binding in tau‐PET negative patients with clinical Alzheimer’s disease

Abstract

AbstractBackgroundDifferent tau‐PET patterns have been observed in Alzheimer’s disease (AD) which may be associated with demographic factors, copathology and resilience. We and others previously found that not all Aβ‐positive AD patients are tau‐PET positive. It is currently not known whether tau pathology develops in these groups over time. Therefore, we aimed to examine longitudinal tau binding in tau‐PET negative individuals with symptomatic AD.MethodWe included 97 Aβ‐positive participants with clinical diagnosis of mild cognitive impairment or dementia due to AD (MCI/AD) of which 12 (13%) were tau‐PET negative. To compare, we included 131 tau‐PET negative cognitively unimpaired individuals (CU) of which 93 (71%) were Aβ‐negative and 38 (29%) Aβ‐positive. Tau‐status was defined by [18F]flortaucipir PET consensus visual read of two nuclear physicians according to US Food and Drug Administration‐approved guidelines. [18F]flortaucipir SUVr at baseline (N = 225) and after ±2 years (N = 81) was quantified in an early tau region reflecting Braak I (entorhinal cortex), the medial temporal lobe (MTL), and a combined visual read region of interest (ROI) (parietal, occipital, and posterior lateral temporal lobe). We used age‐and sex‐adjusted linear mixed models to compare tau accumulation.ResultDemographics are shown in table 1. Compared to MCI/AD A+T+, MCI/AD A+T‐ were older (p<0.001) and more often male (p = 0.015). MCI/AD A+T‐ did not differ from CU A‐T‐ in baseline tau‐PET SUVr, but had a slightly lower SUVr in Braak I compared to CU A+T‐ (p = 0.040) (figure 1). After ±2 years, all MCI/AD A+T‐ participants who underwent follow up remained visual read tau negative. However, MCI/AD A+T‐ showed a steeper increase in Braak I and MTL tau‐PET SUVr compared to CU A‐T‐ (figure 2A,B) and in Braak I compared to CU A+T‐ (β = 0.31, p = 0.036). Interestingly, MCI/AD A+T‐ showed a significantly steeper tau‐PET SUVr increase compared to MCI/AD A+T+ in Braak I (β = 0.29, p = 0.029) (figure 2A).ConclusionAlthough visual read tau‐PET status remains stable over time, our results indicate that tau‐negative MCI/AD patients do accumulate tau over time, most pronounced in early tau regions. This highlights the relevance of quantifying tau regionally over time in tau‐PET negative individuals with clinical AD diagnosis.