Aging of the brain is considered the major risk factor for incidence of Alzheimer’s Disease (AD). It is therefore important to investigate abnormalities in the human brain in healthy elderly controls and in subjects with mild cognitive impairment (MCI). Although MCI can be caused by other pathologies, subjects with MCI are at increased risk of developing AD dementia(1) and can thus be used to investigate prodromal AD biomarkers. The presence of the e4-allele of the Apolipoprotein E (APOE) gene is the major genetic risk factor for sporadic AD (2). Compared to individuals not carrying any e4-allele, the risk for developing AD is increased by a factor of ca. 3 in subjects carrying one e4-allele, and by a factor of ca. 10-30 for homozygote carriers (two e4-alleles). Cerebrovascular dysfunction has been associated with aging, MCI and AD (3). Most studies to date report alterations in total cerebral blood volume (CBV) and flow (CBF) (including arterial, capillary and venous vessels) in the brain without specific information on which vascular components are involved. Neurophysiology studies have shown that small arteries and arterioles are most responsive to changes in metabolism. Recent evidence from animal models demonstrates that aging affects pial arteries and arterioles before capillaries and venous vessels, and that dysfunction in pial arteries occurs months before total CBF change can be observed (4). Thus, the study of changes in such arterial vessels may provide a useful marker that reflects brain changes at an earlier disease stage compared to structural and other measures that are commonly used currently. In this study, the inflow-based vascular-space-occupancy (iVASO) MRI technique (5-7) was applied to investigate potential abnormality in the combined cerebral blood volume of pial arteries and arterioles (CBVa) in the grey matter (GM) of the brain in elderly subjects with MCI. The association between GM CBVa and APOE-e4 carrier-status in these subjects was also assessed. Participants: Eighteen subjects with MCI (11male, 7female; 75.0±7.2yr, three subjects did not complete all required scans and thus were excluded from analysis) and twenty-two healthy elderly controls (14male, 8female; 72.0±5.3yr) were scanned. Twelve of the subjects carried one e4-allele and two subjects carried two e4-alleles. All participants received neuropsychiatric examination and were screened for cognitive impairment (Mini Mental State Examination (8) and Montreal Cognitive Assessment (9)). Subjects were categorized either as cognitively normal or MCI according to established criteria (10). MRI: 7T Philips MRI scanner, 32-channel phased-array head coil. Anatomical images were acquired with MP2RAGE (TR/TE=6.9ms/2.0ms, voxel=0.75mm isotropic). GM CBVa was measured using 3D iVASO MRI with whole brain coverage: TR/TI=10000/1383, 5000/1093, 3800/884, 3100/714, 2500/533, and 2000/356ms; 3D TFE readout, TR_TFE/TE_TFE=4.2/2.2ms; voxel=3.5x3.5x5mm³, 20 slices; SENSE=2x2; crusher gradients of V_enc=10cm/s on z-direction. Image analysis: SPM8, AIR and in-house code programmed in Matlab6.0 (Mathworks, USA) were used. Partial volume effects of WM and CSF on the iVASO signals in GM were corrected. CBVa maps were generated using the iVASO theory (5). Statistical analysis: Two-sample t-tests were performed to examine group differences in GM CBVa in the whole brain on a voxel-by-voxel basis. Correlation between CBVa and APOE-e4 carrier-status was evaluated using data combined from all subjects (including MCI and controls) by calculating the adjusted R² from linear regression. Multiple comparisons were corrected with the false discovery rate (FDR) approach. The IBASPM116 atlas (PickAtlas, WFU) was used to identify anatomical regions within the significant clusters.Figure 1 and Table 1 summarize the main findings from the group comparison. The average GM CBVa values in controls were all in normal range (5), providing validation for our measurements. Significant elevation of GM CBVa was detected in several brain regions in MCI patients compared to controls with relative changes of 49.5-122.0% and effect sizes of 0.79-1.33. Significant reduction of GM CBVa was also observed in a few brain regions. Figure 2 shows that GM CBVa in the orbitofrontal cortex significantly correlated (positive) with APOE-e4 carrier-status from all subjects.We report significant regional abnormalities of GM CBVa in subjects with MCI in various brain regions such as frontal, temporal, insular and olfactory cortex, and the hippocampus. Many of these regions have been implicated as signature regions for neurodegenerative brain change in AD. Relevance of our findings for AD pathology is further supported by the correlation between GM CBVa in orbitofrontal cortex and APOE-e4 carrier-status. Further longitudinal studies are required to validate its potential use as biomarker in clinical trials for early intervention in elderly populations at increased risk for AD.