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Basic Science and Pathogenesis.
Inez K A Pranoto1,2, Katherine W Hui1,2, Tiara A Schwarze-Taufiq1,2
1Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 23, 2025
Summary
Antidepressants and bladder antimuscarinics increase dementia risk by causing neurotoxicity and altering amyloid-beta peptide processing. These common anticholinergic drugs directly impact neuronal function, contributing to Alzheimer's disease development.
Area of Science:
- Neuroscience
- Pharmacology
- Stem Cell Biology
Background:
- Anticholinergic medications are widely used by older adults.
- Evidence links certain anticholinergics (antidepressants, bladder antimuscarinics) to increased dementia risk.
- Confounding by indication complicates direct causal links.
Purpose of the Study:
- To investigate the direct effects of anticholinergic drugs on dementia-related cellular phenotypes.
- To elucidate the molecular mechanisms by which these drugs affect neuronal function.
Main Methods:
- Generated 16 human induced pluripotent stem cell (hiPSC) lines from Adult Changes in Thought (ACT) participants.
- Differentiated hiPSC lines into cortical neurons (hiPSC-Ns).
- Treated hiPSC-Ns with antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics at varying concentrations and timepoints; assessed neurotoxicity, amyloid-beta (Aβ) peptide ratios, and tau phosphorylation.
Main Results:
- Antidepressants and bladder antimuscarinics induced dose- and time-dependent neurotoxicity.
- These drug classes increased the Aβ42/Aβ40 ratio, indicating pathogenic amyloid precursor protein processing.
- Oxybutynin showed the highest Aβ42/Aβ40 ratio increase; no changes in tau phosphorylation were observed.
Conclusions:
- Antidepressants and bladder antimuscarinics induce neurotoxicity and pathogenic Aβ secretion.
- Findings validate a direct link between these anticholinergic drugs and dementia risk.
- The study provides molecular insights into drug-induced neuronal dysfunction contributing to Alzheimer's disease.
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