Biomarkers

Background: Characterizing factors that impact longitudinal tau progression is important for understanding tau heterogeneity observed in clinical trials and research. This work examined factors associated with longitudinal tau PET (¹⁸F-MK-6240) accumulation relative to onset of entorhinal tau (EC) to better understand neurofibrillary tangle (NFT) spatial accumulation in Alzheimer's disease.

Method: Participants (N=595; Table 1) from the Wisconsin Registry for Alzheimer's Prevention and WADRC underwent serial amyloid and tau PET imaging. Amyloid burden was quantified from global cortical ¹¹C-PiB DVR_(0-70). Tau burden was quantified in regions of interest (ROIs) corresponding to Braak NFT1-6 using ¹⁸F-MK-6240 SUVR_(70-90). Sampled iterative local approximation (SILA) was used to model EC tau trajectories and estimate EC tau-time and onset age and, separately, to estimate amyloid level at tau scan. Regional tau accumulation was modeled with mixed effects models separately for Braak NFT2-6 as a function of EC tau-time (i.e. years of EC T+) starting with cubic polynomials. Models also included EC tau-time*estimated CL at baseline tau (due to known associations between amyloid and tau) and additionally examined EC tau-time interactions with age at baseline tau, self-reported sex, and APOEe4.

Result: In this largely unimpaired cohort, there were no significant differences observed in APOEe4 carriage, baseline clinical status or amyloid level, or estimated age of A+ or EC T+ onset across males and females (Table 1). Regional T+ followed the expected spatiotemporal pattern (NFT2-6) as time from EC T+ onset increased (Figure 1A). Across NFT3-6, ROIs outside the medial temporal lobe (MTL), female sex and higher baseline amyloid were each associated with significantly faster tau accumulation rates relative to EC tau-time (Figure 1A-B). Post-hoc comparisons indicated that rates of tau accumulation relative to EC tau-time increased sequentially with increasing levels of amyloid, and that in NFT3-6, the average rate of tau accumulation was significantly faster for females compared to males (Table 2).

Conclusion: These findings provide evidence that tau accumulation and spread outside the MTL is accelerated by higher levels of amyloid and female sex. These data suggest that while people follow a similar spatial progression, the rate of progression varies, which may inform tau-related dementia prediction.