Anticholinergic drugs and dementia risk: Using stem cell-based studies to complement pharmacoepidemiology

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.