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

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-02-05 DOI:10.1002/trc2.70040

Tiara A. Schwarze-Taufiq, Inez K. A. Pranoto, Katherine Hui, Chizuru Kinoshita, Onchee Yu, Paul K. Crane, Shelly L. Gray, Jessica E. Young

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引用次数: 0

Abstract

BACKGROUND

Anticholinergic (AC) use remains common in older adults despite evidence of safety risks, including increased risk in dementia. Pharmacoepidemiology studies from various populations report associations between specific anticholinergic classes – antidepressants and bladder antimuscarinics – and increased dementia incidence. However, it is difficult to determine whether these associations are directly caused by the neurotoxic effects of anticholinergic drugs or by the underlying health conditions which the medications are taken for, known as confounding by indication. Here, we leverage human induced pluripotent stem cells-derived-neurons (hiPSC-Ns) to complement the pharmacoepidemiology studies by directly examining the effects of various anticholinergic classes on dementia-related cellular phenotypes.

METHODS

We treated human induced pluripotent stem cell (hiPSC)–derived neurons with eight drugs representing different AC medication classes, including antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics. We analyzed these neurons for cytotoxicity, amyloid beta (Aβ) peptide levels in the conditioned medium, and the level of intracellular phosphorylated tau from these cultures.

RESULTS

We observed that antidepressants and bladder antimuscarinics were consistently cytotoxic, whereas antihistamines and antispasmodics did not show overt cytotoxicity at the times and concentrations that we tested. Some of the cytotoxic medications altered the amounts of Aβ1-42 peptides, but there were no significant differences in the intracellular ratio of phosphorylated tau/total tau between AC drug treatments.

CONCLUSIONS

These results corroborate population-based studies and suggest a molecular basis for the differences in dementia risk observed according to AC class. This warrants future work examining the effect of AC medications on hiPSC-derived cells from multiple subjects and examining other molecular outcomes including synaptic function and neuroinflammation in hiPSC-based models.

Highlights

Certain classes of anticholinergic (AC) medications are linked to dementia.
Human-induced pluripotent stem cell (hiPSC) models are used to directly test the cytotoxicity of AC medications.
AC classes that are associated with dementia are more neurotoxic.

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.