Background:Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in regulating synaptic activity and plasticity.Objective:Given that type-2 diabetes (T2DM) increases the risk of cognitive decline, and studies have suggested lower BDNF levels may be a risk factor of diabetic neurovascular complications, we sought to investigate total white matter hyperintensities (WMH) as a moderator of the effect of BDNF on hippocampal volume and cognition.Methods:Older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative (N = 454 including 49 with T2DM and 405 without diabetes) underwent neuropsychological evaluation, magnetic resonance imaging to quantify hippocampal and WMH volumes, and blood draw to assess BDNF.Results:Adjusting for age, sex, andAPOEɛ4 carrier status, there was a significant interaction between total WMH and BDNF on bilateral hippocampal volume in the non-T2DM group (t= 2.63,p= 0.009). Examination of main effect models with a dichotomous high/low BNDF group revealed a significant main effect for low BDNF (t= –4.98,p< 0.001), such that as WMH increased, bilateral hippocampal volume decreased. There was also a significant interaction between total WMH and BDNF on processing speed in the non-T2DM group (t= 2.91,p= 0.004). There was a significant main effect for low BDNF (t= –3.55,p< 0.001) such that as WMH increased, processing speed decreased. The interactions were not significant in the T2DM group.Conclusion:These results further elucidate the protective role that BDNF plays on cognition, as well as the cognitive effects of WMH.