Amyloid-β and tau-PET imaging

All participants had a brain PET scan with [¹⁸F]MK-6240, a tracer with adequate specificity for tau neurofibrillary tangles.^32,33 They also had amyloid-β plaques imaging performed with the [¹⁸F]AZD4694 (otherwise known as [¹⁸F]NAV4694) tracer. PET data were acquired with a Siemens High Resolution Research Tomograph (HRRT) (point-spread function of 2.4-mm full-width half-maximum). [¹⁸F]MK-6240 images were acquired 90–110 minutes post-injection, and the [¹⁸F]AZD4694 images were acquired 40–70 minutes post-injection. Images were reconstructed with the ordered subset expectation maximization algorithm on a four-dimensional volume with 300-second frames (four frames for [¹⁸F]MK-6240 and six frames for [¹⁸F]AZD4694).³⁴ Following each PET scan, a 6-minute transmission scan was conducted with a rotating point of ¹³⁷Cs source for attenuation correction. Images underwent corrections for dead time, decay, random and scattered coincidences.

We obtained PET image transformation matrices from linear PET registration to the bias field corrected T1w image space. In parallel, T1w images were linearly and non-linearly registered to the ADNI template space. These transformations were concatenated and applied to the PET image using Advanced Normalization Tools.³⁵ PET images were spatially smoothed using an 8-mm full-width half-maximum Gaussian kernel. Standardized uptake value ratio (SUVR) maps were generated using the inferior cerebellar grey matter as a reference region for [¹⁸F]MK6240 images and the whole cerebellar grey matter as a reference region for [¹⁸F]AZD4694 scans.^34,36 We obtained global amyloid-PET signal on average SUVRs from the precuneus, prefrontal, orbitofrontal, parietal, temporal, anterior and posterior cingulate cortices.³⁷ Participants were categorized as either amyloid-β positive (A+) or negative (A−) based on a threshold that has been validated specifically for [¹⁸F]AZD4694 scans using data from the same cohort (SUVR > 1.55).^38,39 We established hippocampal tau positivity (T+) or negativity (T−) based on the average SUVR in the Braak stage II area (Supplementary Fig. 1), surpassing a threshold established in a previous TRIAD study (SUVR > 0.9940).⁴⁰ We chose Braak stage II as it is mostly contained within the hippocampus while attained at an early stage, with abnormalities preceding cognitive decline.⁴⁰ This region of interest (ROI) is mostly made up of the hippocampus body and the posterior half of the head, with a smaller cluster situated within the entorhinal cortex.