Repetitive negative thinking is associated with amyloid accumulation over 3 years in cognitively healthy adults

Importance: Identifying potentially modifiable risk factors for Alzheimer's disease (AD) is a priority. Repetitive negative thinking (RNT) is a modifiable cognitive-emotional process common to many psychological risk factors for AD, including anxiety and depression. The psychological debt hypothesis proposes that RNT may itself increase risk for AD. Objective: To determine whether RNT symptoms are associated with change in established neurobiological markers of AD risk over time. Design: Longitudinal neuroimaging study with the IMAP/IMAP+ cohort. Setting: Monocentric with community-dwelling participants. Participants: 94 cognitively healthy adults aged 21-89 years (average 57.41 SD 18.31, 55% female) with up to 3 neuroimaging scans over a 3-year period. Exposure: All participants completed validated measures of RNT, anxiety and depression symptoms. Main Outcome(s) and Measure(s): Change over time in global cortical amyloid (Florbetapir-PET), glucose metabolism (FDG-PET), and structural grey matter volume (MRI) adjusted for potential confounders. PET images were corrected for partial volume effects, and AD-relevant masks were used for all neuroimaging outcomes. Post-hoc analyses divided the predictor variable into tertiles to aid visualisation, and FDR-corrected voxel-wise analyses were performed to identify region-specific changes. Results: RNT was associated with increasing global amyloid accumulation even after controlling for psychological symptoms (B = 0.0120, 95% Confidence Interval 0.003 to 0.021, P = 0.012), and in sensitivity analyses limited to participants aged ≥50 or ≥60. Post-hoc tests showed a significant difference in rate of amyloid accumulation between the lowest and highest RNT tertiles (P=0.008). Voxelwise analyses revealed that RNT predicted significantly faster increases in regions vulnerable to early amyloid accumulation in AD (e.g. precuneus, posterior cingulate cortex, and medial frontal cortex). RNT was not associated with change in glucose metabolism or brain atrophy (Ps>0.05). Neither anxiety nor depressive symptoms were associated with change in any neuroimaging outcome (Ps>0.05). Conclusions and Relevance: Higher RNT was associated with more rapid accumulation of cortical amyloid in regions affected early in AD. These findings indicate that this transdiagnostic cognitive-emotional process may be an early marker and/or driver of AD pathology. Given that RNT is responsive to treatment, future research is needed to investigate whether modifying RNT reduces AD risk.