Objective: To investigate the effects of vascular risk factors and APOE status on white matter microstructure, and subsequent cognitive decline among older people.Methods: This study included 241 participants (age 60 years and older) from the populationbased Swedish National Study on Aging and Care in Kungsholmen in central Stockholm, Sweden, who were free of dementia and stroke at baseline (2001)(2002)(2003)(2004). We collected data through interviews, clinical examinations, and laboratory tests. We measured fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging, and estimated volume of white matter hyperintensities using automatic segmentation. We assessed global cognitive function with the Mini-Mental State Examination at baseline and at 3-and/or 6-year follow-up. We analyzed the data using multivariate linear regression and linear mixed models.Results: Heavy alcohol consumption, hypertension, and diabetes were significantly associated with lower FA or higher MD (p , 0.05). When aggregating heavy alcohol consumption, hypertension, and diabetes together with current smoking, having an increasing number of these 4 factors concurrently was associated with decreasing FA and increasing MD (p trend , 0.01), independent of white matter hyperintensities. Vascular risk factors and APOE e4 allele interacted to negatively affect white matter microstructure; having multiple ($2) vascular factors was particularly detrimental to white matter integrity among APOE e4 carriers. Lower tertile of FA and upper tertile of MD were significantly associated with faster Mini-Mental State Examination decline.Conclusions: Vascular risk factors are associated with reduced white matter integrity among older adults, which subsequently predicted faster cognitive decline. The detrimental effects of vascular risk factors on white matter microstructure were exacerbated among APOE e4 carriers. Neurology ® 2015;84:1128-1135 GLOSSARY DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; MD 5 mean diffusivity; MMSE 5 Mini-Mental State Examination; SNAC-K 5 Swedish National Study on Aging and Care in Kungsholmen; WMH 5 white matter hyperintensity.Population-based studies have linked some individual vascular risk factors (e.g., hypertension and diabetes) to reduced microstructural white matter integrity.1-3 However, few studies have explored the relationship of clustering vascular risk factors to white matter microstructure. This is important because vascular factors often occur concurrently in older people. Moreover, as white matter hyperintensities (WMH) and reduced white matter microstructure may share a common ischemic origin, it is of interest to explore whether associations between vascular risk factors and lower microstructural white matter integrity are independent of WMH.Vascular risk factors contribute to cognitive decline in aging, but the mechanisms are poorly understood. 4 One possibility is that vascular risk factors may cause cognitive decline by conferring detrimental impact on white matter mi...