Hypoperfusion in early-phase amyloid PET as a predictor of cognitive decline in Alzheimer's disease

Dual-phase amyloid PET enables concurrent assessment of amyloid burden and cerebral perfusion, providing both molecular and functional information within a single visit. While amyloid PET is well validated diagnostically, the prognostic value of early-phase perfusion remains less explored. We aimed to determine whether perfusion in Alzheimer’s disease (AD)–relevant regions is associated with longitudinal cognitive trajectories. We analyzed 218 participants from a memory-clinic cohort ranging from cognitively unimpaired (CU, n = 65) to mild cognitive impairment (MCI, n = 115) and dementia (n = 38). Based on visual read of late-phase amyloid PET, 123 participants were classified as amyloid-positive (Aβ+) and 93 as amyloid-negative (Aβ–). The groups differed significantly in age, education, and baseline MMSE (all p < 0.01), but not in sex distribution. Early-phase perfusion was quantified as standardized uptake value ratios (SUVr) within an AD meta–region of interest (posterior cingulate, angular, and temporal cortex) and analyzed using linear mixed-effects models adjusting for age, sex, education, APOE ε4 genotype, and white matter lesion burden. Among Aβ+ participants, 11 were CU, 79 MCI, and 33 dementia; among Aβ– participants, 53 were CU, 35 MCI, and 5 dementia. Perfusion declined progressively across clinical stages (CU > MCI > dementia) and was positively correlated with baseline MMSE (r = 0.39, p < 0.001). In Aβ+ individuals, higher baseline perfusion predicted slower MMSE decline over time (interaction β = 5.85, p < 0.001), whereas no such association was observed in the Aβ– group. No significant association was observed in amyloid-negative participants. These effects remained significant after adjustment for vascular and genetic covariates and were independent of amyloid plaque burden. Perfusion derived from early-phase amyloid PET in AD-related regions is a reliable marker of cognitive status and progression in individuals with confirmed amyloid pathology. These findings highlight the added value of dual-phase PET as a practical, single-visit approach for combined diagnostic and prognostic evaluation, particularly where additional functional imaging is not feasible.