Aging modulates amyloid clearance kinetics during anti-amyloid therapy: evidence from real-world serial amyloid PET.

BACKGROUND: Anti-amyloid antibodies have been shown to reduce cerebral amyloid burden in early Alzheimer's disease (AD), yet considerable interindividual variability in treatment-associated amyloid reduction has been observed. The biological factors underlying this variability remain unclear. In particular, the influence of aging on amyloid clearance dynamics during anti-amyloid therapy has not been well characterized in real-world clinical settings. METHODS: We conducted a prospective observational study of 23 patients with early-stage AD receiving lecanemab who underwent serial 18F-flutemetamol amyloid PET at baseline and after 6 and 12 months. Amyloid burden was quantified in centiloid units. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Baseline cerebral perfusion was evaluated using 123I-IMP SPECT with three-dimensional stereotactic surface projection (3D-SSP) analysis. RESULTS: All participants showed reductions in amyloid burden on serial PET; however, the magnitude of reduction varied substantially across individuals. Older patients tended to exhibit larger and more rapid reductions in amyloid burden, whereas younger patients demonstrated more modest decreases despite comparable baseline amyloid levels and standardized dosing. Amyloid reduction at 6 months strongly predicted the magnitude of reduction at 12 months, suggesting that early PET changes capture subsequent amyloid clearance trajectories. Cognitive decline occurred in a subset of patients despite substantial amyloid reduction and was associated with marked baseline temporo-parietal hypoperfusion on SPECT rather than insufficient amyloid removal. CONCLUSION: In this real-world cohort, aging appeared to influence the observable kinetics of amyloid reduction during anti-amyloid therapy. Early serial amyloid PET may provide useful information regarding longer-term amyloid dynamics, while baseline perfusion imaging may help identify patients with substantial downstream neurodegenerative burden who remain at risk for cognitive decline despite amyloid clearance. These findings highlight biological heterogeneity in treatment response and underscore the value of multimodal imaging for monitoring disease-modifying therapies in AD.