Image acquisition and processing - BioFINDER-2 cohort

MRI was performed using a Siemens 3T MAGNETOM Prisma scanner (Siemens Medical Solutions). Structural T1-weighted MRI images were acquired from a magnetization-prepared rapid gradient echo (MPRAGE) sequence with 1 mm isotropic voxels. PET images were acquired on digital GE Discovery MI scanners. For tau-PET, acquisition was done 70–90 min post injection of ~370 MBq [¹⁸F]RO948. For Aβ-PET, acquisition was done 90–110 min post injection of ~185 MBq [¹⁸F]Flutemetamol. Images were processed according to our pipeline described previously⁵⁷. Briefly, PET images were attenuation corrected, motion corrected, summed and registered to the closest T1-weighted MRI processed through the longitudinal pipeline of FreeSurfer version 6.0. Standardized uptake value ratio (SUVR) images were created using the inferior cerebellar gray matter as the reference region for [¹⁸F]RO948⁵⁸, and the pons for [¹⁸F]Flutemetamol. PET SUVR images were then warped non-linearly to the Montreal Neurological Institute (MNI152) template space using Advanced Normalization Tools (ANTs) version 2.3.1⁵⁹ registration parameters of the T1-weighted MRI scan to the MNI152 template.

The cutoff for Aβ-positivity was 0.53 SUVR, defined from Gaussian mixture modeling (GMM) on a neocortical global Aβ region of interest (prefrontal, lateral temporal, parietal, anterior cingulate, and posterior cingulate/precuneus), as used previously¹⁵. This cutoff was used to classify CU and MCI participants, and a cutoff from CSF was used in AD dementia patients.

[¹⁸F]RO948 signal can be affected by off-target binding in the skull and meninges³³. Given that the analyses focused on whole-brain cortical regions, we excluded a few participants with high levels of skull/meningeal binding, using a similar approach as described previously⁶⁰. We calculated the SUVR ratio of a meningeal/skull mask to the average SUVR from GM, WM and CSF masks. Participants with a ratio above 1.75 were excluded, the latter having more than 1.75 times greater binding in the off-target region than in the brain. After such quality control, 12 CU Aβ-negative, 4 CU Aβ-positive, 2 MCI Aβ-positive participants and 1 AD dementia patient with longitudinal tau-PET were excluded from the final sample.