{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:03:25Z","timestamp":1785420205149,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,21]]},"group-title":"Neuroscience","reference-count":26,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["K08NS128329"],"award-info":[{"award-number":["K08NS128329"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01NS136122"],"award-info":[{"award-number":["R01NS136122"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Davis Alzheimer Prevention Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    Anti-amyloid immunotherapy is used to treat Alzheimer disease (AD) with moderate benefits and potentially serious side effects due to amyloid related imaging abnormality with effusions\/edema (ARIA-E). Different anti-amyloid antibodies have different\n                    <jats:italic>in vitro<\/jats:italic>\n                    binding characteristics to different synthetic A\u03b2 aggregates, leading to the assumption that they bind different species in the human brain. Lecanemab is hypothesized to bind \u201cprotofibrils,\u201d but these are not well-characterized in human brain. It is also unknown how binding differences correlate with ARIA-E rates. The\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    allele increases ARIA-E risk, but how it affects antibody binding characteristics is unknown.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To determine whether anti-amyloid antibodies bind different species of human brain A\u03b2 and whether these binding properties to human brain A\u03b2 explains ARIA-E rates.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Cross-sectional study of 18 postmortem human brains.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Setting<\/jats:title>\n                  <jats:p>Single tertiary care hospital.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Participants<\/jats:title>\n                  <jats:p>Deceased patients with AD and cerebral amyloid angiopathy (CAA).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcomes and Measures<\/jats:title>\n                  <jats:p>\n                    Equilibrium binding constants (K\n                    <jats:sub>D<\/jats:sub>\n                    ) and total A\u03b2 binding (B\n                    <jats:sub>max<\/jats:sub>\n                    ) of recombinant aducanumab, lecanemab, and donanemab equivalents to human brain soluble and insoluble amyloid plaque-enriched and CAA-enriched A\u03b2 aggregates.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Lecanemab did not bind with greater affinity to the soluble fraction of A\u03b2 compared to aducanumab. All three antibodies were bound essentially identical quantities of A\u03b2 across the 18 cases and fractions (Pearson\u2019s r 0.84 \u2013 0.97). Antibody preference for plaque\n                    <jats:italic>vs<\/jats:italic>\n                    CAA A\u03b2 did not differ in soluble fractions but differed slightly in insoluble extracts. The\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    allele led to a more soluble antibody-accessible A\u03b2 pool in a dose-dependent manner for all three antibodies.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions and Relevance<\/jats:title>\n                  <jats:p>\n                    The lecanemab binding target in human brain is unlikely to be distinctly \u201cprotofibrillar\u201d compared to other antibodies. Differences in antibody preference for plaque\n                    <jats:italic>vs<\/jats:italic>\n                    CAA A\u03b2 are unlikely to fully explain differences in ARIA-E rates. The\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    allele may plausibly increase ARIA-E risk by making antibody-accessible A\u03b2 more soluble. These results have implications for improving the safety and efficacy of current and future anti-amyloid antibody therapies.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.20.654902","type":"posted-content","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T19:55:14Z","timestamp":1747857314000},"source":"Crossref","is-referenced-by-count":5,"title":["Anti-amyloid antibody equilibrium binding to A\u03b2 aggregates from human Alzheimer disease brain"],"prefix":"10.64898","author":[{"given":"P. Monroe","family":"Butler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Francis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela L.","family":"Meunier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirah K.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L.","family":"Hennessey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Lemere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis J.","family":"Selkoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8589-6891","authenticated-orcid":false,"given":"Andrew 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