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Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of A\u03b2, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce A\u03b2 plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE\u2009=\u200914\/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6\u00a0mg\/kg, for a cumulative dose of 186\u00a0mg\/kg. In the LTE, Amyloid PET scans demonstrated robust A\u03b2 plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to\u2009&lt;\u20091.1 at 56\u00a0weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4\u00a0months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. A\u03b2 and IBA1 immunohistochemistry assays demonstrated sparse residual A\u03b2 plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA\/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V\u2013VI, NIA\/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce A\u03b2 plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab\u2019s mechanism of action and impact on AD biomarkers.<\/jats:p>","DOI":"10.1007\/s00401-022-02433-4","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T13:18:47Z","timestamp":1652793527000},"page":"143-153","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Alzheimer disease neuropathology in a patient previously treated with aducanumab"],"prefix":"10.1007","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9016-4751","authenticated-orcid":false,"given":"Edward D.","family":"Plowey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Bussiere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Rajagovindan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Sebalusky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Hamann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"von Hehn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Castrillo-Viguera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Sandrock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Budd Haeberlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher H.","family":"van Dyck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Huttner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"2433_CR1","doi-asserted-by":"publisher","first-page":"6412","DOI":"10.1038\/s41598-018-24501-0","volume":"8","author":"JW Arndt","year":"2018","unstructured":"Arndt JW, Qian F, Smith BA, Quan C, Kilambi KP, Bush MW et al (2018) Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-beta. 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Plowey is an employee and shareholder of Biogen. Thierry Bussiere is an employee and shareholder of Biogen. Jennifer Sebalusky is an employee and shareholder of Biogen. Stefan Hamann is an employee and shareholder of Biogen. Carmen Castrillo-Viguera is an employee and shareholder of Biogen. Samantha Budd Haeberlein is an employee and shareholder of Biogen. Raj Rajagovindan was an employee of Biogen when this work was conducted, is a shareholder of Biogen and is currently an employee of Vigil. Christian von Hehn was an employee of Biogen when this work was conducted. Christian von Hehn is not a shareholder of Biogen. Alfred Sandrock was an employee of Biogen when this work was conducted and is a shareholder of Biogen. Christopher H. van Dyck was a PRIME and EMERGE trial site investigator. He is a consultant for Roche, Eisai, Ono, and Cerevel and receives research support from Biogen, Eisai, Roche, Genentech, Eli Lilly, Janssen, Merck, Novartis, and Biohaven. Anita Huttner has no competing interests to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Autopsy authorization, consent to utilize tissues for research and consent to publish was obtained according to Connecticut state law and approved protocols of the Yale University BioBank. The research study was approved by the Yale Alzheimer Disease Research Center (ADRC) and was reviewed and deemed exempt by the Yale University Institutional Review Board. The BioBank protocols are in accordance with the ethical standards of Yale University. Clinical and radiologic data were collected per the 221AD103 Study Protocol as previously published [\n                      \n                      ]. The Phase 1b PRIME study consent included permission to publish clinical data in the context of future research studies.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consents"}}]}}