Title: Amyloid Clearance and Heterogeneous Downstream Tau Responses After Donanemab: A Three-Case PET Study

Background: Donanemab has been approved for the treatment of mild cognitive impairment due to AD and mild AD dementia. Its effect to reduce amyloid protein has been established. However, the extent of amyloid clearance after short-term treatment and its association with downstream tau pathology, cerebral glucose metabolism, and clinical outcomes remain unclear. Therefore, we described the different PET evaluation and clinical changes in three patients with mild AD before and after donanemab treatment.

Method: Three middle-aged to elderly patients with mild AD (A+T+N+ by PET) received donanemab after multidisciplinary evaluation and informed consent. Patients were followed for six months. Cognitive assessments and amyloid, tau, and FDG PET imaging were performed at baseline and at 24 weeks to evaluate amyloid burden, tau pathology, and cerebral metabolism. Amyloid-related imaging abnormalities (ARIA) were monitored throughout treatment.

Result: Cognitive function remained stable over 24 weeks. No symptomatic amyloid-related imaging abnormalities were observed. Cases A and B (APOE ε3/ε4) achieved amyloid clearance in Centiloid values (Case A: −25.43 to −12.99; Case B: 51.75 to −15.96). Case A showed tau PET clearance. Case B showed a marked reduction. FDG-PET still showed hypometabolism in selected brain regions. Case C (APOE ε3/ε3) showed modest amyloid reduction (SUVR 1.56 to 1.51). No change was observed on tau PET or FDG PET. A single asymptomatic microhemorrhage occurred before the fourth infusion in Case C. Treatment was continued. No further ARIA events occurred.

Conclusion: These cases show heterogeneous biomarker responses after 24 weeks of donanemab treatment. Two patients achieved amyloid clearance in Centiloid values. Tau PET showed clearance in one case and reduction in another. One patient showed only modest amyloid reduction without downstream changes. All patients remained clinically stable. One asymptomatic microhemorrhage occurred and treatment was continued. These findings suggest variable downstream responses after amyloid removal. Larger studies are needed to confirm these observations.