Introduction Anti-amyloid immunotherapies are approved by the United States Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease. The adoption and safety profile of these medications in routine clinical practice have not been described.

Methods We performed a retrospective observational cohort study using nationwide electronic health record data from Epic Cosmos. The principal objective was to describe the baseline characteristics of patients prescribed anti-amyloid immunotherapy in routine clinical practice. Secondarily, we wished to determine whether prescription of anti-amyloid immunotherapy (with or without an acetylcholinesterase inhibitor [AChEI] or memantine) was associated with an increased risk of key safety end points when compared to an AChEI or memantine alone. We used a target trial emulation framework to identify and mitigate sources of bias. The primary end point was time to first nontraumatic intracranial hemorrhage (ICH). Secondary end points included other cardiovascular conditions (ischemic stroke (IS), myocardial infarction (MI), and a composite of ICH, IS, or MI), headache, diarrhea and overall healthcare utilization. Exploratory end points included adverse events linked to other immunotherapies. We used propensity score overlap weighting to balance baseline demographic and clinical characteristics across treatment groups.

Results Between July 1, 2023 and January 1, 2025, 2,616 patients (median age 74.8 years [IQR 69.8-78.8]; 53.9 % female) were prescribed anti-amyloid immunotherapy (with or without AChEI/memantine), and 1,065,192 patients (median age 79.98 [IQR 73.6-85.6], 57.9% female) were prescribed AChEI/memantine alone. In total, 401 patients prescribed anti-amyloid immunotherapy and 274,470 patients prescribed AChEI/memantine were assessed for safety end points. Compared with AChEI/memantine, prescription of anti-amyloid immunotherapy was not associated with increased hazard of ICH after adjustment (owHR 0.73 [95% CI 0.11-5.46]). Anti-amyloid immunotherapy prescription was associated with a higher risk of headache (owHR 2.16 [95% CI 1.12-4.16]) and respiratory infection (owHR 1.57 [95% CI 1.04-2.37]) but was not associated with other immune-related safety endpoints.

Conclusion Anti-amyloid immunotherapy has been principally adopted by patients who are younger and medically healthier than patients receiving AChEI/memantine alone. Prescription of anti-amyloid immunotherapy was not associated with an increased risk of ICH.

JBL discloses grant funding from the Alzheimer's Association, National Institute on Aging, American Heart Association, and the Duke University Office of the Provost and committee service (uncompensated) for the American Heart Association. KVF reports no relevant disclosures. KGJ discloses research consulting for the University of Southern California, speaker fees from Eisai Inc., and primary investigator relationships with Eisai Inc, LEXEO Therapeutics, Athira Pharma, Annovis Bio, and the Critical Path Institute. AL discloses consulting for Lucent. JLL reports no relevant disclosures. LET reports no relevant disclosures. RM discloses grant funding from Duke University Office of the Provost, Arnold Ventures, Washington Center for Equitable Growth, and the American Investment Council. McDevitt has received consulting fees through the American Society of Nephrology and Charles River Associates as well as speaker fees from Welsh, Carson, Anderson, & Stowe, InTandem Capital, and Heritage Group. AZ reports no relevant disclosures. HW reports no relevant disclosures. RO reports no relevant disclosures. SA reports no relevant disclosures. BGH reports no relevant disclosures. BM discloses research funding from grant K23HL161426 from the National Heart, Lung, and Blood Institute, grant 23MRFSCD1077188 from the American Heart Association, grant 2835124 from the Duke Office of Physician Scientist Development, and through Bayer Pharmaceuticals as a site principal investigator. FL reports no relevant disclosures. EO discloses research funding from the Alzheimer's Association.

This work was funded by the Duke-UNC Alzheimer's Disease Research Center via a Research Education Component grant to Dr. Lusk (NIA P30AG072958) and by the Duke University Office of the Provost. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board of the University of North Carolina Chapel Hill waived ethical approval for this work (review number 459493).

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Funding Sources and Role of the Sponsor: This work was funded by the Duke-UNC Alzheimer’s Disease Research Center via a Research Education Component grant to Dr. Lusk, (NIA P30AG072958) and by the Duke University Office of the Provost. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agency had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest Disclosures:

JBL discloses grant funding from the Alzheimer’s Association, National Institute on Ageing, American Heart Association, and the Duke University Office of the Provost and committee service (uncompensated) for the American Heart Association.

KVF reports no relevant disclosures.

KGJ discloses research consulting for the University of Southern California, speaker fees from Eisai Inc., and primary investigator relationships with Eisai Inc, LEXEO Therapeutics, Athira Pharma, Annovis Bio, and the Critical Path Institute.

AL discloses consulting for Lucent.

JLL reports no relevant disclosures.

LET reports no relevant disclosures.

RM discloses grant funding from Duke University Office of the Provost, Arnold Ventures, Washington Center for Equitable Growth, and the American Investment Council. McDevitt has received consulting fees through the American Society of Nephrology and Charles River Associates as well as speaker fees from Welsh, Carson, Anderson, & Stowe, InTandem Capital, and Heritage Group.

AZ reports no relevant disclosures.

HW reports no relevant disclosures.

RO reports no relevant disclosures.

SA reports no relevant disclosures.

BGH reports no relevant disclosures.

BM discloses research funding from grant K23HL161426 from the National Heart, Lung, and Blood Institute, grant 23MRFSCD1077188 from the American Heart Association, grant 2835124 from the Duke Office of Physician Scientist Development, and through Bayer Pharmaceuticals as a site principal investigator.

FL reports no relevant disclosures.

EO discloses research funding from the Alzheimer’s Association.

Data can be obtained from Epic Systems under an approved institutional Data Use Agreement for Epic Cosmos.