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INTRODUCTION Lecanemab binds “protofibrils,” which are poorly characterized in human brain. It is unknown why lecanemab caused fewer amyloid‐related imaging abnormalities (ARIAs) than other antibodies in trials. The apolipoprotein E (APOE) ε4 allele increases ARIA risk through unknown mechanisms. METHODS Equilibrium binding constants (KD) and total amyloid beta (Aβ) binding (Bmax) of aducanumab, lecanemab, and donanemab equivalents to soluble and insoluble amyloid plaque‐enriched and cerebral amyloid angiopathy (CAA)‐enriched Aβ were compared across 17 Alzheimer's disease (AD) cases by mixed models. Titrated immunofluorescence (IF) staining compared antibody binding. RESULTS Lecanemab and aducanumab had indistinguishable preference for “protofibrils.” Antibody preference for plaque‐enriched versus CAA‐enriched Aβ did not differ in soluble extracts or by IF staining but differed slightly in insoluble extracts. The APOE ε4 allele was associated with more soluble antibody‐accessible Aβ. DISCUSSION Lecanemab's binding target is similar to other antibodies’. Differences in antibody preference for plaque versus CAA Aβ may not explain differences in ARIA with edema rates. Highlights We tested binding of clinical anti‐amyloid antibodies to human brain amyloid beta (Aβ). Lecanemab, donanemab, and aducanumab bound similar populations of Aβ. The apolipoprotein E ε4 allele increased solubility of antibody‐bound Aβ.

Understanding the hazards of space radiation is imperative as astronauts begin voyaging on missions with increasing distances from Earth’s protective shield. Previous studies investigating the acute or long-term effects of specific ions comprising space radiation have revealed threats to organs generally considered radioresistant, like the brain, and have shown males to be more vulnerable than their female counterparts. However, astronauts will be exposed to a combination of ions that may result in additive effects differing from those of any one particle species. To better understand this nuance, we irradiated 4-month-old male and female, wild-type and Alzheimer’s-like mice with 0, 0.5, or 0.75 Gy galactic cosmic ray simulation (GCRsim) or 0, 0.75, or 2 Gy gamma radiation (wild-type only). At 11 months, mice underwent brain and heart MRIs or behavioral tests, after which they were euthanized to assess amyloid-beta pathology, heart and kidney gene expression and fibrosis, and plasma cytokines. Although there were no changes in amyloid-beta pathology, we observed many differences in brain MRIs and behavior, including opposite effects of GCRsim on motor coordination in male and female transgenic mice. Additionally, several genes demonstrated persistent changes in the heart and kidney. Overall, we found sex- and genotype-specific, long-term effects of GCRsim and gamma radiation on the brain, heart, and kidney.

INTRODUCTION Vervets are non‐human primates that share high genetic homology with humans and develop amyloid beta (Aβ) pathology with aging. We expand current knowledge by examining Aβ pathology, aging, cognition, and biomarker proteomics. METHODS Amyloid immunoreactivity in the frontal cortex and temporal cortex/hippocampal regions from archived vervet brain samples ranging from young adulthood to old age was quantified. We also obtained cognitive scores, plasma samples, and cerebrospinal fluid (CSF) samples in additional animals. Plasma and CSF proteins were quantified with platforms utilizing human antibodies. RESULTS We found age‐related increases in Aβ deposition in both brain regions. Bioinformatic analyses assessed associations between biomarkers and age, sex, cognition, and CSF Aβ levels, revealing changes in proteins related to immune‐related inflammation, metabolism, and cellular processes. DISCUSSION Vervets are an effective model of aging and early‐stage Alzheimer's disease, and we provide translational biomarker data that both align with previous results in humans and provide a basis for future investigations. Highlights We found changes in immune and metabolic plasma biomarkers associated with age and cognition. Cerebrospinal fluid (CSF) biomarkers revealed changes in cell signaling indicative of adaptative processes. TNFRSF19 (TROY) and Artemin co‐localize with Alzheimer's disease pathology. Vervets are a relevant model for translational studies of early‐stage Alzheimer's disease.

Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer’s-like and wildtype littermate mice 7–8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer’s model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.