Increased brain uptake of ¹⁸F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (V_T) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min ¹⁸F-AV45 (291 ± 67 MBq) and 1-min ¹⁵O-H₂O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). ¹⁸F-AV45 V_T was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min after injection, using either cerebellar gray matter (SUVR_CB) or whole subcortical white matter (SUVR_WM) as the reference. Additionally, whole cerebellum, pons, centrum semiovale, and a composite region were examined as alternative references. Blood flow was quantified by ¹⁵O-H₂O SUV. Data are presented as mean ± SEM. Results: There was rapid metabolization of ¹⁸F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with V_T, differences in cortical Aβ load between aMCI and AD were overestimated by SUVR_WM (+4% ± 2%) and underestimated by SUVR_CB (-10% ± 2%). V_T correlated better with SUVR_WM (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, P < 0.0001) than with SUVR_CB (Pearson r: from 0.51 for temporal lobe [P = 0.002] to 0.82 for precuneus [P < 0.0001]) in all tested regions. Correlation results for the alternative references were in between those for CB and WM. ¹⁵O-H₂O data showed that blood flow was decreased in AD compared with aMCI in cortical regions (-5% ± 1%) and in the reference regions (CB, -9% ± 8%; WM, -8% ± 8%). Conclusion: Increased brain uptake of ¹⁸F-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVR_WM is better correlated with V_T and more closely reflects V_T differences between aMCI and AD than SUVR_CB.

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