Tau pathology as determinant of changes in atrophy and cerebral blood flow. A multi-modal longitudinal imaging study

Tau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF. We included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-β positive [Aβ +], 26 cognitively impaired [CI]) who underwent dynamic [${}^{18}$F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [${}^{18}$F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [${}^{18}$F]flortaucipir PET binding potential (BP${}_{ND}$) and R${}_1$ values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BP${}_{ND}$ in Braak I, III/IV, and V/VI regions and cortical thickness or R${}_1$ in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BP${}_{ND}$ in case of analyses with annual change as determinant. All analyses were performed in Aβ- cognitively normal (CN) individuals and Aβ+ (CN and CI) individuals separately. In Aβ + individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aβ+ or Aβ- individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aβ + individuals. We showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal.