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.

Abstract Image

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抗胆碱能药物与痴呆风险：利用干细胞为基础的研究补充药物流行病学

背景：尽管有证据表明抗胆碱能药物存在安全风险，包括痴呆风险增加，但在老年人中抗胆碱能药物（AC）的使用仍然很普遍。来自不同人群的药物流行病学研究报告了特定抗胆碱能类药物——抗抑郁药和膀胱抗胆碱药——与痴呆发病率增加之间的联系。然而，很难确定这些关联是由抗胆碱能药物的神经毒性作用直接引起的，还是由药物治疗的潜在健康状况直接引起的，这被称为指征混淆。在这里，我们利用人类诱导多能干细胞衍生的神经元（hiPSC-Ns）来补充药物流行病学研究，直接检查各种抗胆碱能类药物对痴呆相关细胞表型的影响。方法：我们用8种代表不同AC药物类别的药物治疗人诱导多能干细胞（hiPSC）来源的神经元，包括抗抑郁药、膀胱抗毒菌素、抗组胺药和抗痉挛药。我们分析了这些神经元的细胞毒性，条件培养基中的β淀粉样蛋白（Aβ）肽水平，以及细胞内磷酸化tau水平。结果：我们观察到抗抑郁药和膀胱抗蛇毒素始终具有细胞毒性，而抗组胺药和抗痉挛药在我们测试的时间和浓度下没有表现出明显的细胞毒性。一些细胞毒性药物改变了Aβ1-42肽的数量，但在AC药物治疗之间，细胞内磷酸化tau/总tau的比例没有显著差异。结论：这些结果证实了基于人群的研究，并提示根据AC类别观察到的痴呆风险差异的分子基础。这保证了未来研究AC药物对来自多个受试者的hipsc衍生细胞的影响，以及在基于hipsc的模型中研究其他分子结果，包括突触功能和神经炎症。某些类别的抗胆碱能（AC）药物与痴呆有关。采用人诱导多能干细胞（hiPSC）模型直接检测AC药物的细胞毒性。与痴呆相关的AC类更具有神经毒性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.