Cerebral microvascular physiology associated with white matter lesion burden differs by level of vascular risk in typically aging older adults

White matter lesions (WMLs) are prevalent with aging, and higher WML burden has been observed in older adults with vascular diseases. While the physiology underlying the formation of WMLs is not known, various risk factors are associated with high WML burden. Here, we investigated the relationship between vascular risk factors and microvascular physiology (i.e., oxygen supply and oxygen extraction fraction [OEF]) and their association with WML burden. Forty-one typically aging adults (60-80 years) were classified into high or low vascular risk based on common modifiable vascular risk factors (hypertension, diabetes, hyperlipidemia, and overweight). These groups were subdivided into high or low WML burden. Differences in microvascular physiology (oxygen supply and OEF) were then compared between and within groups. Overall, OEF was significantly higher in the high vascular risk group compared to the low vascular risk group (p < 0.01). In the low vascular risk subgroup, OEF was uniquely lower in the individuals with high WML versus low WML burden (p = 0.02), despite no differences in oxygen supply between these subgroups (p = 0.87). The coupling of impaired OEF with the absence of compensatory physiology, such as elevated oxygen supply, may represent an important mechanism underlying WML burden in individuals with low vascular risk factors.