The aging brain is characterized by distinct pathological alterations that include extracellular accumulation of Amyloid-β (Aβ) and associated neuronal damage as indicated by increased regional iron load as well as progressive loss of brain tissue. While these changes promote cognitive decline and risk for neurodegenerative brain-disorder, of which Alzheimer’s disease (AD) is the most frequent, a minority of elderly subjects display significantly higher cognitive performance levels and less brain atrophy. This fortunate subset of the elderly population is referred to as "super-agers", as they appear to outperform their age-group in terms of resilience against age-related brain pathologies. In previous work (ISMRM15 #4663) our group demonstrated the presence of correlated local Aβ load and iron levels (as estimated by Quantitative Susceptibility Mapping, QSM1,2) to be associated with mild cognitive impairment (MCI) and AD-risk (APOEe4 carrier status) in elderly subjects. The main objective of the current study was to investigate the degree of association between cortical Aβ and regional iron-load in cognitively normal super-agers by simultaneous assessment of QSM MRI and 18F-Flutemetamol-PET. 25 cognitively normal and medically healthy individuals of high age (Table 1) were studied using a 3T SIGNA General-Electrics Healthcare combined PET-MR instrument. All participants received medical and psychiatric examination, as well as standardized neuropsychological assessment to assure normal cognitive function in cognitive subdomains. Significant brain pathologies were excluded by visual inspection of MRI-scans (by P.G.U.). A T1-weighted BRAVO image (voxel size=1x1x1mm3) was acquired for segmentation using a multi-atlas approach2,3. Regions of interest were eroded by 2 pixels before being applied as a mask in further processing. QSM images were reconstructed from a 3D multi-echo GRE sequence (TR/TE/ΔTE=40/3/4ms, voxel size=1x1x1mm3, flip angle=15°) using the echoes with echo time between 15 and 27ms. Sequentially, Laplacian phase unwrapping, V-SHARP for background removal4 and an LSQR based approach for dipole inversion5 were used to create the QSM image. After removal of the background field, the resulting images of the 4 echoes were averaged to obtain a higher signal to noise ratio as compared to single echo reconstruction6. The frontal cerebral spinal fluid region (CSF) in the lateral ventricles region showed least inter and intra subject variability and was selected as a reference region for the final susceptibility quantification. All reported susceptibility values are relative to this reference region. Aβ-plaque density was estimated by PET acquisition of 18F-Flutametamol7 (85-105 minutes post injection) and reconstructed using time-of-flight reconstruction (voxel size=1.2x1.2x2.78mm3) for calculation of standardized uptake value ratios (SUVR). The PET image was segmented using the parcellation created from the T1-weighted image and all PET-values were then referenced to the cerebellar gray matter. Mean cortical gray matter PET values and visual inspections were used to group subjects into a high or low Aβ-load group.The assessed cortical gray matter 18F-Flutametamol SUVRs showed a two - peak distribution within the study population, allowing the separation of participants with high values (n=6, "Aβ-positive", Figure 1, top) versus participants with low values (n=19, "Aβ-negative", Figure 1, bottom). When comparing local iron load between the Aβ-positive and Aβ-negative groups, significant differences (p-FDR-corrected < 0.05) while controlling for gender could be observed for the left and right caudate nucleus and left and right putamen (Figure 2, average of left and right). The Aβ-positive and Aβ-negative groups did not differ on any cognitive measure. Rank order correlation analysis did not indicate significant correlation between local iron load and local Aβ-load for any of the 60 gray matter regions of the atlas. To our knowledge, this is the first report indicating a significant association of cortical Aβ-plaque load with iron accumulation in basal ganglia gray-matter nuclei of cognitively normal super-agers, as reflected by increased susceptibility in right and left caudate nucleus and putamen. The co-occurrence of both high basal-ganglia susceptibility and cortical Aβ-plaque burden may indicate a higher degree of aging-related brain change in this subset of the study population. As local Aβ and iron levels generally do not show significant relationships in the investigated population, both may represent independent phenomena that occur together due to a shared age-related liability. Therefore, our data suggest that while super-agers may be affected by common age-related brain pathologies as indicated by cortical Aβ-plaque burden in combination with increased basal-ganglia iron, these might exert less neurotoxic damage, as reflected by lack of regional correlation and normal performance in cognitive testing.