Temporal Association of Imaging Biomarkers of Cerebrovascular Disease and Alzheimer’s Disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) pathologic changes (e.g. amyloid and tau aggregation), and cerebrovascular disease often coexist, and it remains unclear whether these are mechanistically linked processes (Graff‐Radford, Brain 2019; Provenzano, JAMA Neurol 2013). Most studies evaluating these associations are cross‐sectional; however, establishing temporal relationships may provide additional insight into potential mechanistic associations. One method to assess the temporal evolution of a biomarker is the Accelerated Failure Time (AFT) model, which assumes a common pattern of progression for a given biomarker that is shifted earlier or later in time for each individual (Therneau, Neuroimage 2021). In this work we investigate the relationship of disease trajectories of cerebrovascular disease (via white matter hyperintensity, WMH, volume) and AD biomarkers (via amyloid and tau PET).MethodsWe included Mayo Clinic Study of Aging (MCSA) and Mayo Alzheimer’s Disease Research Center (ADRC) participants with amyloid PET, tau PET, and MRI, age > 50 years, and a clinical diagnosis of cognitively unimpaired (CU), mild cognitive impairment (MCI) or Alzheimer’s disease dementia. The AFT model was fit with amyloid PET (PiB) global meta‐ROI SUVR, tau PET (flortaucipir) temporal meta‐ROI SUVR, and WMH volume as the tri‐variate endpoints, with APOE genotype, sex, education, total intracranial volume, and referral/population subject as covariates. A per subject/endpoint random effect represents individual adjustments for each biomarker to indicate if the subject's biomarker became abnormal earlier or later relative to their demographic peers, accounting for the covariates.ResultsThe study included 1144 participants (Table 1). There was a strong correlation between earlier onset of amyloid and earlier onset of tau (r=0.64, CI=0.60‐0.67) (Figure 1, Table 2); early/late amyloid timing explained nearly half (0.642 = 41%) of the variation in tau onset. There were only weak associations between an individual’s WMH and amyloid PET onset adjustments (r=0.10, 1.0%) and WMH and tau PET onset adjustments (r=‐0.07, 0.5%).ConclusionThis analysis supports a strong mechanistic relationship between amyloid and tau aggregation, as reported by others. However, our findings do not support a mechanistic association between WMH and amyloid or tau PET.