# Translational pharmacoepidemiology: neuroprotection and neurotoxicity of antihypertensives and strong anticholinergics

> **NIH NIH U19** · KAISER FOUNDATION RESEARCH INSTITUTE · 2021 · $669,884

## Abstract

PROJECT 3 ABSTRACT
Medications are an important exposure in the life course epidemiology framework that ties the Adult Changes in
Thought (ACT) U19 Program together. Medications for chronic conditions are taken over several years, often
beginning in mid-life, and chronic regimens achieve consistent blood levels, so toxic or protective brain effects
of medication exposures are plausible. The Adult Changes in Thought (ACT) study has served as an incredible
resource for cutting-edge dementia pharmacoepidemiology research for over 20 years. We take a multifaceted
approach to examine links between common drugs and brain health by using an array of brain-related measures
in the same cohort to deepen our understanding about these relationships and mechanisms. A considerable
methodologic issue inherent in pharmocoepidemiology research is confounding by indication, where the
condition for which a drug is prescribed is associated with dementia rather than the drug itself. In this Project,
we take an innovative and translational approach to complement our existing pharmacoepidemology methods
by deploying molecular assays that will directly address confounding by indication bias with a cell-based model
using human induced pluripotent stem cell (hiPSC)-derived neurons (hiPSC-Ns) from ACT participants. The
following Aims will be accomplished by working directly with all Project Cores. Aim 1: Deploy a human stem cell-
based molecular assay to directly test mechanisms of neurotoxicity from anticholinergics (AChs) and address
confounding by indication. We will deploy assays that measure four cellular outcomes: AD pathological
molecules, Ab and pTau; neurotoxicity; and neuronal function. Aim 2: To determine comparative associations of
antihypertensives (AHTs) with dementia and AD (2A), neuropathology (2B), and neuroimaging outcomes (2C),
and test mechanisms of neuroprotection (2D). We will test the hypotheses that after controlling for their effects
on blood pressure, exposure to Ang-II↑ drugs compared with Ang-II↓ drugs is associated with lower risk of
dementia and AD, neuropathology and neuroimaging outcomes. We will test the hypothesis that Ang-II↑ drugs
will have positive effects on cellular outcomes (i.e: Aβ and pTau, neurotoxicity and neuronal function) compared
with an Ang-II↓ drug using the group of hiPSC-derived neurons developed in Aim 1.
Our Project has important

## Key facts

- **NIH application ID:** 10168318
- **Project number:** 1U19AG066567-01A1
- **Recipient organization:** KAISER FOUNDATION RESEARCH INSTITUTE
- **Principal Investigator:** SHELLY L GRAY
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $669,884
- **Award type:** 1
- **Project period:** 2021-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168318

## Citation

> US National Institutes of Health, RePORTER application 10168318, Translational pharmacoepidemiology: neuroprotection and neurotoxicity of antihypertensives and strong anticholinergics (1U19AG066567-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10168318. Licensed CC0.

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