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New England Journal of Medicine, Volume 390, Issue 1, Page 55-62, January 2024.

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To the Editor The TRAILBLAZER-ALZ 2 trial provided additional evidence that the APOE4 genotype is a risk factor for amyloid-related imaging abnormalities, especially cerebral edema and effusion. These findings are consistent with those from other clinical trials of β-amyloid–targeting monoclonal antibodies in patients with Alzheimer disease. During donanemab treatment, amyloid-related imaging abnormalities of edema/effusion were observed in only 15.7% of APOE ε4 noncarriers but in 22.8% of heterozygous carriers and 40.6% of homozygous APOE ε4 carriers. These neuroimaging abnormalities were mostly asymptomatic and resolved in approximately 10 weeks. In approximately 1.6% of donanemab-treated participants, amyloid-related imaging abnormalities resulted in serious outcomes such as brain bleeding or swelling and even death, which occurred in 3 participants. A JAMA Editorial and other groups have recommended that APOE genotyping be performed to assess risk for amyloid-related imaging abnormalities before initiating treatment with this class of monoclonal antibodies. Among persons diagnosed with Alzheimer disease, up to 60% carry at least 1 APOE ε4 allele and are consequently at increased risk of amyloid-related imaging abnormalities. Thus, it is unclear how determination of the APOE genotype alone will guide donanemab treatment of this large subgroup of patients with Alzheimer disease. In the donanemab trial and in studies with other monoclonal antibodies, APOE ε4 carriers and noncarriers have received the same drug dose regimen. Cerebrospinal fluid (CSF) donanemab drug levels were not reported. Thus, it is unknown whether pharmacokinetic factors, such as higher CSF drug exposure, may have contributed to the higher risk of amyloid-related imaging abnormalities in APOE ε4 carriers. Increased amyloid burden associated with APOE ε4 and a more pronounced immune response have generally been suggested as factors contributing to the increased amyloid-related imaging abnormalities associated with this genotype. However, there is evidence that the APOE ε4 genotype may also be associated with a disruption of the blood-brain barrier. Breakdown of the blood-brain barrier may result in increased drug entry into the central nervous system that could have important safety implications because adverse events are generally dose-dependent. We would be grateful if Dr Sims and colleagues could discuss any data or insights they may have on the possible role of higher CSF donanemab levels in the increased risk for amyloid-related imaging abnormalities associated with the APOE ε4 genotype. If the hypothesized association is confirmed, determination of the APOE ε4 genotype together with emerging biomarkers of blood-brain barrier disruption, such as CSF and plasma-soluble platelet-derived growth factor receptor β, could provide a target for more individualized donanemab dose regimens to minimize the risk of serious amyloid-related imaging abnormalities.

In Reply Amyloid-related imaging abnormalities are a common adverse event for individuals with Alzheimer disease receiving amyloid-targeting therapies. In their Letter, Drs Pomara and Imbimbo thoughtfully explore the possibility that APOE-mediated breakdown of the blood-brain barrier could lead to increased concentrations of donanemab in the CSF and thus increase incidence of amyloid-related imaging abnormalities (edema and effusions). This hypothesis is important to consider.

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This Viewpoint explains the genetic association between Alzheimer disease and Down syndrome and the negative impact of excluding people with Down syndrome from clinical trials on treatment for Alzheimer disease.