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The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

An Addendum to this article was published on 22 June 2017


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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Figure 1: Amyloid plaque reduction with aducanumab: example amyloid PET images at baseline and week 54.
Figure 2: Amyloid plaque reduction with aducanumab.
Figure 3: Aducanumab effect (change from baseline) on CDR-SB and MMSE.
Figure 4: Reduction of amyloid burden following weekly dosing with chaducanumab in 9.5- to 15.5-month-old Tg2576 transgenic mice.
Figure 5: Aducanumab binds selectively to insoluble fibrillar and soluble oligomeric Aβ aggregates.

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These studies were funded by Biogen. The authors thank the patients and their family members participating in the aducanumab studies, and the PRIME investigators (Supplementary Information) and staff conducting these studies. Medical writing support, under direction of the authors, was provided by A. Smith at Complete Medical Communications, and was funded by Biogen. We thank N. Pederson, J. Dolnikova and E. Garber for help in generating the recombinant antibodies, D. Fahrer, C. Quigley, M. Themeles, X. Zhang and P. Auluck for help in generating the histological data, and K. Mack for editorial support and coordination of the authors in combining the preclinical and clinical work in this manuscript.

Author information

Authors and Affiliations



T.B., P.H.W., M.M., T.E., K.R., J.G. and R.M.N. designed the preclinical studies, and J.S., Y.L., J.G., J.F., C.H., R.M.N. and A.S. designed the clinical study. P.C. led the imaging implementation for the clinical study. T.C. and J.O. were clinical study statisticians. T.B., P.H.W., M.M., R.D., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., J.G. and R.M.N. generated, analysed, and/or interpreted data from preclinical studies. T.B., P.H.W., M.M., R.D., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., K.R., J.G., C.H., R.M.N. and A.S. critically reviewed preclinical sections of the manuscript. J.S., P.C., L.W., S.S., T.C., Y.L., J.O., J.F., Y.H., A.M., J.G., C.H., R.M.N. and A.S. analysed and interpreted clinical study data and critically reviewed clinical sections of the manuscript. All authors approved the final version of the manuscript for submission. Biogen and Neurimmune reviewed and provided feedback on the paper. The authors had full editorial control of the paper, and provided their final approval of all content.

Corresponding author

Correspondence to Alfred Sandrock.

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Competing interests

J.S., P.C., T.B., P.H.W., L.W., R.D., T.C., Y.L., J.O., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., K.R., J.F., Y.H., A.M. and A.S. are current or former employees and/or shareholders of Biogen. J.S. is an employee of F. Hoffmann-La Roche Ltd., Basel, Switzerland; R.D. is an employee of AbbVie Inc., Worcester, Massachusetts, USA; M.A. is an employee of Substantial Living, San Francisco, California, USA; M.L. is an employee of Novartis, Cambridge, Massachusetts, USA; S.C. is an employee of SynteractHCR, Carlsbad, California, USA; O.Q.-M. is an employee of Shire, Lexington, Massachusetts, USA; R.H.S. and K.R. are employees of Yumanity Therapeutics, Cambridge, Massachusetts, USA; T.E. is an employee of Takeda Pharmaceuticals, Cambridge, Massachusetts, USA; J.F. is retired. M.M., J.G., C.H. and R.M.N. are employees and shareholders of Neurimmune. S.S. was a site investigator for the PRIME study and received consultation fees from Biogen, and has received research support from Functional Neuromodulation, Merck, Genentech, Roche, Lilly, and Avid Radiopharmaceuticals, and consultation fees from Merck, Piramal, Lilly, Genentech, and Roche. He owns no stock options or royalties. Biogen has filed and licensed certain patent applications pertaining to Aducanumab.

Additional information

Reviewer Information Nature thanks L. Lannfelt, R. Thomas and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Participant accounting.

PET, positron emission tomography.

Extended Data Figure 2 Amyloid plaque reduction with aducanumab by baseline clinical stage and baseline ApoE ε4 status.

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.

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.

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.

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.

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.

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 Table 1 Change from baseline in amyloid PET SUVR values (a secondary endpoint at 6 months), and in exploratory clinical endpoints at the end of the placebo-controlled period (6-month data also shown for amyloid PET)
Extended Data Table 2 Incidence of ARIA based on MRI data and ARIA-E patient disposition
Extended Data Table 3 Pharmacokinetic data
Extended Data Table 4 Change from baseline in amyloid PET SUVR values, CDR-SB, and MMSE at the end of the placebo-controlled period by absence/presence* of ARIA-E

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Sevigny, J., Chiao, P., Bussière, T. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

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