The relationship between VEGF and cerebral vascular territory glucose metabolism is modified by cardiovascular risk in Alzheimer's disease

Abstract

AbstractBackgroundVascular endothelial growth factor (VEGF) regulates angiogenesis, neurogenesis, and glucose transport. Cardiovascular risk factors promote atherosclerosis and disrupt vascular integrity, possibly interfering with VEGF function. Variability in cardiovascular dysfunction severity may explain an inconsistent neuroprotective effect of VEGF across Alzheimer’s disease (AD) studies. Atherosclerosis in the middle and posterior cerebral arteries is associated with AD. We hypothesize that a higher Framingham Risk Score (FRS), a proxy for atherosclerosis severity, will moderate the association between VEGF and glucose metabolism in brain regions supplied by the MCA and PCA.MethodIn 158 participants (age: 55‐90 years; 39 normal, 80 MCI, 39 AD; 105M/53F) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we evaluated whether CSF VEGF levels were associated with bilateral glucose metabolism (FDG‐PET) in gray matter vascular territories supplied by the anterior (ACA), middle (MCA), and posterior cerebral arteries (PCA), each defined by the vascular territory MNI template (Figure‐1, Figure‐2). We evaluated whether FRS modified the regional relationship between VEGF (Figure‐3) and FDG‐PET across all participants and within each diagnostic group. We used a mixed effects linear regression model (covarying for age, sex, education, APOE4 carrier status, CSF T‐tau, and diagnosis; random effect=site). All p‐values presented are false discovery rate (FDR) corrected at FDR <5%.ResultHigher VEGF was associated with higher FDG‐PET MCA‐SUVR (β=0.170, p=0.043), nominally associated with higher PCA‐SUVR (β=0.129, p=0.078), and not associated with ACA‐SUVR (β=0.092, p=0.244). In all participants, FRS nominally modified the association between VEGF and ACA‐SUVR (VEGF‐FRS interaction β=‐0.040, p=0.066) and MCA‐SUVR (VEGF‐FRS interaction β=‐0.032, p=0.066). In MCI participants alone, FRS significantly modified the association between VEGF and both ACA‐SUVR (VEGF‐FRS interaction β=‐0.078, p=0.014) and MCA‐SUVR (VEGF‐FRS interaction β=‐0.068, p=0.014).ConclusionThe region‐specific negative interaction of FRS with CSF VEGF suggests that higher VEGF levels were associated with greater MCA territory glucose metabolism in persons with lower FRS. Greater cardiovascular dysfunction may dampen VEGF’s neuroprotective effects, particularly in MCA‐supplied brain regions and in populations at risk for AD.