Reductions in biomarkers of Alzheimer's disease pathophysiology following treatment with aducanumab were associated with slowing in clinical decline. (December 2021)

• Record Type: Journal Article
• Authors: Rajagovindan, Raj; Chen, Tianle; Nisenbaum, Laura; Tian, Ying; Muralidharan, Kumar Kandadi; Dent, Gersham; He, Ping; Castrillo‐Viguera, Carmen; Haeberlein, Samantha Budd
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.057499
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) and tau in the brain. Aducanumab is a human monoclonal antibody that selectively targets aggregated forms of Aβ. In clinical studies, aducanumab treatment resulted in dose‐ and time‐dependent reduction in Aβ levels accompanied by slowed clinical decline. Method: Participants in the Phase 1b PRIME study (NCT01677572) were randomized to receive aducanumab (1, 3, 6, or 10 mg/kg [fixed‐dose or titrated]) or placebo every 4 weeks (q4w). The effects of aducanumab on clinical endpoints and amyloid positron emission tomography (PET) composite standard uptake value ratio (SUVR) were evaluated at the end of randomization (Week 54). In the Phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) studies, participants were randomized (1:1:1) to received high‐dose aducanumab (10 mg/kg), low‐dose aducanumab (3 mg/kg), or placebo q4w. At Week 78, the effects of aducanumab on clinical endpoints were assessed; the effects on AD biomarkers were assessed in PET and CSF substudies. In the EMERGE and ENGAGE substudies, participant‐level correlations between change from baseline in clinical measures (measured by CDR‐SB, MMSE, ADAS‐Cog 13, and ADCS‐ADL‐MCI) and change from baseline in amyloid PET SUVR or CSF biomarkers (p‐tau and t‐tau) at Week 78 were examined. The same analysis between clinical decline (measured by CDR‐SB and MMSE) and change in amyloid PET SUVR was investigated in PRIME at Week 54. Group‐level correlation between treatment effect on Aβ levels as measured by PET and clinical decline was conducted across all 3 studies. Result: Findings from EMERGE suggest that reduction in AD biomarker levels (amyloid PET, CSF p‐tau, and CSF t‐tau) following treatment with aducanumab are associated with slowing in cognitive decline. Analyses from PRIME are supportive of these findings. In ENGAGE, in which a clinical treatment effect of aducanumab was not observed, correlations were less apparent. However, group‐level analyses based on data from PRIME, EMERGE, and ENGAGE demonstrated a correlation between aducanumab treatment effect on amyloid pathology and clinical measures. Conclusion: The correlation analyses between biomarkers and clinical measures provide evidence that aducanumab‐induced reduction in biomarkers of AD disease pathophysiology is associated with reduced clinical decline.