Neuropathological study of the effects of aducanumab anti-Aβ immunotherapy on patients with Alzheimer’s disease
摘要
Fluid and imaging biomarker data show that anti-amyloid (Aβ) antibodies promote the clearance of Aβ from the brains of patients with Alzheimer’s disease (AD). We examined postmortem brain tissue of individuals who participated in aducanumab clinical trials and investigated the drug’s effects on Aβ pathology and other AD phenotypes. The medial temporal lobe of six aducanumab clinical trial participants—who had extensive exposure to aducanumab and happened to die between 7 weeks and 5 years after their last antibody infusion—was compared with that of nine untreated AD patients matched for age, APOE genotype, and Braak neurofibrillary tangle stage, to determine how aducanumab impacts AD pathobiology. Patients treated with aducanumab displayed a robust reduction in Aβ burden. As observed in previous studies, Aβ was associated with non-arterial microvessels in aducanumab-treated patients, suggesting a redistribution of Aβ within the neuropil. Neuritic phospho-tau decreased in parallel with fewer Aβ plaques, but the density of PHF-1+ and AT8+ neurofibrillary tangles remained unchanged relative to the average untreated AD donor. Measures of microglial and astroglial reactivity were also comparable to those in untreated AD controls. These findings confirm aducanumab’s potent ability to target and remove brain Aβ. On average, Aβ plaques increased in proportion to the length of time after the last dose, consistent with the idea that plaques gradually redeposit post-treatment. The selective reduction of neuritic, but not neurofibrillary tangle phospho-tau implies that Aβ-targeted antibodies such as aducanumab alleviate plaque-associated dystrophy but may not address established tangles. This study describes the long-term outcomes of anti-Aβ immunotherapy in AD.