Objective: Recent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer’s disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI). Methods: Two sets of analyses were conducted. The relationship between whole brain WMH load, based on FLAIR MRI images, obtained in initially cognitively normal participants (n=274) and time to onset of symptoms of MCI (n=60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n=204), the interaction of WMH load and CSF AD biomarkers was also evaluated. Results: Baseline WMH load interacted with CSF t-tau with respect to symptom onset, but not with CSF abeta1-42 or p-tau181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau [HR=1.35, CI=1.06-1.73, p=0.013], but not those with high t-tau [HR=0.86,CI=0.56-1.32, p=0.47]. The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes. Conclusions and Relevance: These results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and non-synergistic effects on the risk of progression to MCI.