2026 ECNP Congress

PS04-4204

Hemolytic anemia as a rare adverse event of donepezil: relevance of hematological monitoring in the treatment of dementia

Federico Carlos Augusto Quaglia — N. Larre · CEMIC, Geriatric Neuropsychiatry Clinic and Psychogeriatric Section. Psychiatry Department., Ciudad Autónoma de Buenos Aires, Argentina

2026 ECNP Congress

Introduction

Donepezil is a widely used acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease and non-Alzheimer dementias [1] [2]. While its safety profile is generally well-established, rare and severe haematological adverse events can pose significant clinical challenges [3]. Drug-induced autoimmune haemolytic anaemia is a particularly infrequent complication that requires prompt identification to prevent serious morbidity in elderly patients [4]. This case highlights the uncommon cold agglutinin-mediated anaemia following the initiation of donepezil for multi-etiology dementia .

Aims

To describe a complex case of suspected drug-induced autoimmune haemolytic anaemia associated with the initiation and dose titration of donepezil in a 76-year-old female.

Methods

This case reports on a 76-year-old female, retired artist, with a significant history of chronic smoking (60 pack-years) and heavy alcohol consumption (up to 0.75 litres of wine daily). The patient was diagnosed with multi-etiology dementia (Alzheimer’s disease, vascular dementia and alcohol-related dementia) following a subacute ischaemic stroke in February 2023. Neuroimaging (MRI) indicated light frontal cortical atrophy (Koedman 2), hippocampal atrophy (MTA 2, left predominance), and chronic microangiopathy (Fazekas 2). Clinical management involved the initiation of donepezil for cognitive symptoms alongside olanzapine and lorazepam for irritability and insomnia. Longitudinal monitoring included serial haematological assays and neurological evaluations over a three-year period.

Results

Following the introduction and titration of donepezil, laboratory results in November 2023 revealed a significant decline in the red blood cell count to 2,210,000/mm³, with a concurrent haemoglobin level of 9.8 g/dl and haematocrit of 29.3%. Morphological analysis suggested the presence of cold agglutinins, leading to a strong suspicion of autoimmune haemolytic anaemia secondary to donepezil treatment. Serum C3 complement “strongly positive”. Serum IgG was negative. Cold agglutinin serology demonstrated markedly elevated titers (1:1024 at 4°C). Other secondary causes of cold agglutinin syndrome (CAS) were excluded as lymphoproliferative, infectious, autoimmune and connective tissue diseases and carcinomas. In accordance with clinical safety protocols, donepezil was discontinued. Subsequent haematological assessments showed a gradual recovery. By July 2024, the red blood cell count rose to 3.98 million/mm³ and haemoglobin stabilised at 12.9 g/dl. In April 2025, haematological parameters remained stable with a haemoglobin level of 12.8 g/dl. Cognitive management was subsequently adjusted through a pharmacological switching to galantamine, starting at 8 mg with a planned titulation to 24 mg per day. During the recovery period, the patient also achieved abstinence from alcohol and a significant reduction in tobacco use, supported by naltrexone. Despite the resolution of the anaemia, the patient continued to show progressive cognitive decline, including anomia and episodic memory impairment.

Conclusions

This case highlights the importance of regular haematological monitoring in patients treated with cholinesterase inhibitors, especially when rare immune-mediated reactions like cold agglutinin-related anaemia are suspected. Clinicians should maintain a high index of suspicion for drug-induced events when laboratory abnormalities coincide with the initiation of anti-dementia therapy. Pharmacological switching to alternative agents like galantamine or rivastigimine remains a viable strategy after the resolution of such adverse events.

References

  1. Birks, J. S. y Harvey, R. J., 2018. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database of Systematic Reviews, (6), Art. No. CD001190. https://doi.org/10.1002/14651858.CD001190.pub3
  2. Fallone, M., Sivananthan, M., & Joseph, M. (2026). Donepezil for Korsakoff Syndrome. American journal of therapeutics, 10.1097/MJT.0000000000002102. Advance online publication. https://doi.org/10.1097/MJT.0000000000002102
  3. Ruangritchankul, S., Chantharit, P., Srisuma, S., & Gray, L. C., 2021. Adverse Drug Reactions of Acetylcholinesterase Inhibitors in Older People Living with Dementia: A Comprehensive Literature Review. Therapeutics and clinical risk management, 17, 927–949. https://doi.org/10.2147/TCRM.S323387
  4. Raja, T., Mayurathan, P., & Sabrina, S., 2025. A Case of Primary Cold Agglutinin-Mediated Hemolytic Anemia Successfully Treated with Steroids. Cureus, 17(7), e87669. https://doi.org/10.7759/cureus.87669
  5. Li, S., Qian, W., Zhang, Z., Chen, Y., Hou, X., Min, B., Zhou, H., Zhu, X., Ling, J., Yang, W., & Cao, S. (2025). Comprehensive safety assessment of donepezil: pharmacovigilance analysis based on the FDA adverse event reporting system. Frontiers in neurology, 16, 1655216. https://doi.org/10.3389/fneur.2025.1655216