Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
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Extended data figures and tables
Extended Data Figures
- Extended Data Figure 1: Participant accounting. (364 KB)
PET, positron emission tomography.
- Extended Data Figure 2: Amyloid plaque reduction with aducanumab by baseline clinical stage and baseline ApoE ε4 status. (437 KB)
a, b, Analyses by baseline clinical stage were performed using ANCOVA for change from baseline with factors of: treatment, ApoE ε4 status (carrier and non-carrier) and baseline composite SUVR (a), and for analyses by ApoE ε4 status, using treatment and baseline composite SUVR (b). Adjusted mean ± s.e. ApoE ε4, apolipoprotein E ε4 allele; SUVR, standard uptake value ratio.
- Extended Data Figure 3: Amyloid plaque reduction: regional analysis SUVR at week 54. (239 KB)
The boxed area indicates the six regions included in the composite score. *P < 0.05; **P < 0.01; ***P < 0.001 versus placebo; two-sided tests with no adjustments for multiple comparisons. Adjusted mean ± s.e. Analyses using ANCOVA. SUVR, standard uptake value ratio.
- Extended Data Figure 4: Brain penetration of aducanumab after a single intraperitoneal administration in 22-month-old Tg2576 transgenic mice. (825 KB)
a, b, Aducanumab levels in plasma and brain (a), and plasma Aβ levels after a single dose (b; n = 4–5; mean ± s.e.). c, d, In vivo binding of aducanumab to amyloid deposits detected using a human IgG-specific secondary antibody (c), and ex vivo immunostaining with a pan-Aβ antibody on consecutive section (d). Examples of a compact Aβ plaque (solid arrow), diffuse Aβ deposit (dashed arrow), and CAA lesion (dotted arrow). CAA, cerebral amyloid angiopathy.
- Extended Data Figure 5: Exposure following weekly dosing with chaducanumab in 9.5- to 15.5-month-old Tg2576 transgenic mice. (386 KB)
a, b, chaducanumab concentrations in plasma (a), or DEA-soluble brain extract (b) were measured in samples collected 24 h after the last dose in the ‘Chronic efficacy study’. Mean ± s.e. Dotted lines represent the limits of quantitation of each assay. c, Correlations of drug concentrations in plasma (open circles) or brain (open triangles) with administered dose. The average brain concentrations in the two groups receiving the lowest dose were below the limit of quantitation for that assay, which is indicated by a dotted line on the figure.
- Extended Data Figure 6: Treatment with chaducanumab affects plaques of all sizes. (1,561 KB)
a, Following weekly dosing of chaducanumab in Tg2576 from 9.5–15.5 months of age, amyloid plaques were stained with 6E10 and quantified using Visiopharm software. b, Plaque size was defined by area, and coloured as follows: <125 μm2 (cyan), 125–250 μm2 (green), 250–500 μm2 (pink), and >500 μm2 (red). c, chaducanumab treatment was associated with a significant decrease in plaque number in all size ranges relative to vehicle-treated controls, with reductions of 58%, 68%, 68%, and 53% in the number of plaques for the <125 μm2, 125–250 μm2, 250–500 μm2, and >500 μm2 groups size, respectively. Mean ± s.e.; statistically significant differences from vehicle for each size range are indicated with asterisks; *P < 0.05, Mann–Whitney test.
- Extended Data Figure 7: Enhanced recruitment of microglia to amyloid plaques following chaducanumab treatment and engagement of Fcγ receptors. (1,273 KB)
a, b, Brain sections from either PBS- or chaducanumab-treated mice (‘Chronic efficacy study’; 3 mg kg−1 group) were immunostained for Aβ (6E10; red) and a marker of microglia (Iba1; brown). c, The area of individual amyloid plaques was measured, and Iba1-stained microglia were grouped into two categories, either associated with plaques (within 25 μm of a plaque) or not associated with plaques (>25 μm from a plaque). Plaques with circumferences ≥ 70% surrounded by microglia were quantified and stratified based on plaque size. The fraction of plaques that were at least 70% surrounded by microglia was significantly greater in the chaducanumab-treated group (white bars) compared with the PBS control group (grey bars), for plaques ≥250 μm2. Mean ± s.e.; statistically significant differences from vehicle for each size range are indicated with asterisks; *P < 0.05, Bonferroni’s post hoc test following one-way analysis of variance. All quantifications were done using the Visiopharm software. d, e, FITC-labelled Aβ42 fibrils were incubated with different concentrations of the antibodies before adding to BV-2 microglia cell line (d), or primary microglia (e) for phagocytosis experiment measuring uptake of Aβ42 fibrils into the cells by FACS analysis. Mean ± s.d.
Extended Data Tables
- Supplementary Information (249 KB)
This includes Supplementary Methods, a Supplementary Discussion and Results, and a list of the PRIME investigators.