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Related Experiment Video

Updated: May 29, 2025

Stereological Estimation of Cholinergic Fiber Length in the Nucleus Basalis of Meynert of the Mouse Brain
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Anticholinergic drugs and dementia risk: Using stem cell-based studies to complement pharmacoepidemiology.

Tiara A Schwarze-Taufiq1,2, Inez K A Pranoto1,2, Katherine Hui1,2

  • 1Department of Laboratory Medicine and Pathology University of Washington Seattle Washington USA.

Alzheimer'S & Dementia (New York, N. Y.)
|February 6, 2025
PubMed
Summary

Certain anticholinergic (AC) medications, like antidepressants and bladder antimuscarinics, are neurotoxic and linked to dementia risk. This study used human stem cell-derived neurons to confirm these AC drug effects.

Keywords:
Alzheimer's diseaseanticholinergicscytotoxicityhuman induced pluripotent stem cellspharmacoepidemiology

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Area of Science:

  • Neuroscience and Pharmacology
  • Stem Cell Biology
  • Drug Safety and Toxicology

Background:

  • Anticholinergic (AC) medications are widely used by older adults, despite known risks including increased dementia incidence.
  • Previous studies suggest links between specific AC classes (antidepressants, bladder antimuscarinics) and dementia, but confounding by indication is a challenge.
  • Human induced pluripotent stem cell-derived neurons (hiPSC-Ns) offer a model to directly assess AC drug neurotoxicity, bypassing confounding factors.

Purpose of the Study:

  • To investigate the direct cellular effects of various anticholinergic medication classes on dementia-related phenotypes.
  • To determine if specific AC drug classes exhibit differential neurotoxicity using a human iPSC-derived neuron model.

Main Methods:

  • Human induced pluripotent stem cell (hiPSC)-derived neurons were treated with eight AC drugs from different classes: antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics.
  • Assessed outcomes included drug-induced cytotoxicity, levels of amyloid beta (Aβ) peptides in conditioned media, and intracellular phosphorylated tau.
  • Concentrations and treatment durations were chosen to mimic potential human exposure levels.

Main Results:

  • Antidepressants and bladder antimuscarinics demonstrated consistent cytotoxicity in hiPSC-Ns.
  • Antihistamines and antispasmodics did not exhibit significant cytotoxicity at tested doses and durations.
  • Cytotoxic AC drugs altered amyloid beta (Aβ1-42) peptide levels, but no significant changes in the phosphorylated tau/total tau ratio were observed.

Conclusions:

  • The findings support population-based studies linking certain AC classes to dementia risk by demonstrating their direct neurotoxic effects in a cellular model.
  • This research suggests a molecular basis for differential dementia risk associated with AC drug classes.
  • Future studies should explore effects on hiPSC-derived cells from diverse subjects and investigate other neurobiological outcomes like synaptic function and neuroinflammation.