Acetaminophen exposure in an aging population and neurodegenerative outcomes
et al., European Journal of Clinical Pharmacology, doi:10.1007/s00228-026-04108-5, Jun 2026
2nd treatment shown to increase risk in
November 2020, now with p = 0.00000029 from 27 studies, but still recommended in 103 countries.
6,600+ studies for
220+ treatments. c19early.org
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Retrospective 581,379 older adults in South Korea showing a dose-dependent association between cumulative acetaminophen use and increased risk of Alzheimer's disease and Parkinson's disease.
Authors hypothesize that acetaminophen's metabolite AM404 and associated mechanisms including neuronal oxidative stress, glutathione depletion, and mitochondrial apoptotic signaling may contribute to neurodegeneration.
(This is not a COVID-19 study - risk of neurodegenerative outcomes with acetaminophen use).
Acetaminophen is also known as paracetamol, Tylenol, Panadol, Calpol, Tempra, Calprofen, Doliprane, Efferalgan, Grippostad C, Dolo, Acamol, Fevadol, Crocin, and Perfalgan.
Kim et al., 16 Jun 2026, peer-reviewed, 2 authors.
Abstract: ## CORRESPONDENCE
Acetaminophen exposure in an aging population and neurodegenerative outcomes
Hye Jun Kim'. Seogsong Jeong' ®
Received: 23 November 2025 / Accepted: 9 June 2026 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2026
Acetaminophen is widely perceived as a safe analgesic, yet even established safety risks may be insufficiently individualized in clinical practice; in a French university hospital study, prescribers infrequently adjusted doses according to hepatotoxicity risk factors [1]. Acetaminophen remains one of the most commonly used analgesics in older adults, although contemporary osteoarthritis guidance discourages routine paracetamol use except for infrequent shortterm pain relief when other pharmacological treatments are contraindicated, not tolerated, or ineffective; similarly, the American College of Rheumatology/Arthritis Foundation conditionally recommends acetaminophen because clinical trial effect sizes are very small [2, 3]. Recent controversy over prenatal acetaminophen and child neurodevelopment epitomizes the difficulty of untangling confounding in pharmacoepidemiology [4, 5]. Beyond developmental windows, acetaminophen's metabolite N-arachidonoylphenolamine (AM404), which engages TRPV1, cannabinoid, serotonergic, and related nociceptive pathways [6, 7]. An experimental study also suggest that acetaminophen can induce neuronal oxidative stress, glutathione depletion, and mitochondrial apoptotic signaling under high-exposure conditions [8]. These data do not establish a direct causal mechanism for Alzheimer's disease (AD) or Parkinson disease (PD), but they provide biological plausibility for investigating long-term neurological outcomes, particularly because oxidative stress and neuroinflammation are shared vulnerability pathways in neurodegenerative diseases [9]. This footprint now indicates a broader question:
This comment refers to the article available online at https://doi.org/1 0.1007/s00228-019-02674-5.
· Seogsong Jeong seogsongjeong@korea.ac.kr
1 Department of Biomedical Informatics, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
does cumulative acetaminophen use erode life-course neural resilience and contribute to late-life neurodegeneration?
We examined this in the Korea National Health Insurance Service-Senior Cohort (NHIS-2025-04-2-117). After exclusions (Supplement Fig. 1), 581,379 older adults who underwent health screening between 2009 and 2010, were followed up until December 31th 2019 (pre-COVID-19). Primary outcomes were incident AD, defined as the International Classification of Diseases 10th Revision (ICD-10) codes F00 and G30 with prescription for donepezil, galantamine, rivastigmine, and memantine, and PD (ICD-10, G20). The exploratory outcomes included speech (ICD-10, R47), symbolic (ICD-10, R48), and voice (ICD-10, R49) disturbances. All follow-up investigation was carried out separately for each outcome. This study adhered to STROBE statement and was approved by the institutional review board of Korea University Guro Hospital (2024GR0376).
Acetaminophen exposure was ascertained from reimbursed prescription records between January 1, 2007, and December 31, 2010. We identified prescriptions containing acetaminophen as either a single-ingredient or combination product based on the claims dataset. For each participant, cumulative exposure was calculated as the total number..
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