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[Preprint]. 2025 May 21:2025.05.20.654902.
doi: 10.1101/2025.05.20.654902.

Anti-amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer disease brain

P Monroe Butler  1 , Anna Francis  1 , Angela L Meunier  1 , Amirah K Anderson  1 , Elizabeth L Hennessey  2 , Michael B Miller  2 , Cynthia A Lemere  1 , Dennis J Selkoe  1 , Andrew M Stern  1
Affiliations

Anti-amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer disease brain

P Monroe Butler et al. bioRxiv. .

Abstract

Importance: 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 in vitro binding characteristics to different synthetic Aβ aggregates, leading to the assumption that they bind different species in the human brain. Lecanemab is hypothesized to bind "protofibrils," but these are not well-characterized in human brain. It is also unknown how binding differences correlate with ARIA-E rates. The APOE ε4 allele increases ARIA-E risk, but how it affects antibody binding characteristics is unknown.

Objectives: To determine whether anti-amyloid antibodies bind different species of human brain Aβ and whether these binding properties to human brain Aβ explains ARIA-E rates.

Design: Cross-sectional study of 18 postmortem human brains.

Setting: Single tertiary care hospital.

Participants: Deceased patients with AD and cerebral amyloid angiopathy (CAA).

Main outcomes and measures: Equilibrium binding constants (KD) and total Aβ binding (Bmax) of recombinant aducanumab, lecanemab, and donanemab equivalents to human brain soluble and insoluble amyloid plaque-enriched and CAA-enriched Aβ aggregates.

Results: Lecanemab did not bind with greater affinity to the soluble fraction of Aβ compared to aducanumab. All three antibodies were bound essentially identical quantities of Aβ across the 18 cases and fractions (Pearson's r 0.84 - 0.97). Antibody preference for plaque vs CAA Aβ did not differ in soluble fractions but differed slightly in insoluble extracts. The APOE ε4 allele led to a more soluble antibody-accessible Aβ pool in a dose-dependent manner for all three antibodies.

Conclusions and relevance: The lecanemab binding target in human brain is unlikely to be distinctly "protofibrillar" compared to other antibodies. Differences in antibody preference for plaque vs CAA Aβ are unlikely to fully explain differences in ARIA-E rates. The APOE ε4 allele may plausibly increase ARIA-E risk by making antibody-accessible Aβ more soluble. These results have implications for improving the safety and efficacy of current and future anti-amyloid antibody therapies.

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Figures

Figure 1.
Figure 1.. Experimental overview.
Occipital lobe grey matter and overlying meninges from 18 cases with AD and CAA were processed to extract aqueously soluble and insoluble fractions. These were immunoprecipitated with serially diluted anti-amyloid antibodies followed by wash, elution, denaturation into monomers, and quantitation of total Aβ42 (for parenchyma) or Aβ40 (for meninges). Binding curves were fit to a one-site specific model and generated a KD, expressed in nM antibody and approximating equilibrium binding affinity, and a Bmax, expressed in ng/ml Aβ and reflecting the total amount of Aβ accessible to the antibody.
Figure 2.
Figure 2.. Binding profiles to insoluble vs soluble parenchymal Aβ42 aggregates.
(A) The log(IS KD ratio) reflects the binding preference of antibodies to insoluble vs soluble aggregates. A higher ratio implies greater preference for soluble aggregates. Donanemab exhibited a log ratio below 0, reflecting a slight preference for insoluble aggregates. Error bars = mean +/− SD. (B) Model estimates for the pairwise mean differences +/− 95% CI in log(IS KD ratio). There was no statistically significant difference between lecanemab and aducanumab, but donanemab had a statistically different ratio compared to lecanemab and aducanumab. (C-F) Correlations between Bmax, the total Aβ accessible to the antibody, across soluble and insoluble extracts reveal near-perfect correlations.
Fig 3.
Fig 3.. Plaque vs CAA antibody binding preferences.
(A, C) The log(MP KD ratio) reflects binding preferences of antibodies to meningeal Aβ40-rich aggregates (CAA-enriched) vs parenchymal Aβ42-rich aggregates (plaque-enriched). A higher ratio implies greater preference for plaque vs CAA aggregates. Error bars = mean +/− SD. (B, D) Model estimates for the pairwise mean differences +/− 95% CI in log(MP KD ratio) reveals no significant differences in the soluble fraction but significant differences in the insoluble fraction. The difference in insoluble log(MP KD ratio) between lecanemab and aducanumab reflects a 1.03- to 2.05-fold greater lecanemab preference for plaque compared to aducanumab, less than the ~2.8-fold difference in phase 3 clinical trials.
Fig 4.
Fig 4.. APOE genotype effects on Aβ accessible to antibody binding.
The log(IS Bmax ratio) reflects the solubility of the Aβ pool accessible to the antibody. A higher log(IS Bmax ratio) reflects a less soluble pool of Aβ. We found that the APOE ε4 dosage increased the solubility (decreased the log(IS Bmax ratio)) of both parenchymal Aβ42 (A) and meningeal Aβ40 antibody targets. Error bars = mean +/− SD.
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