# Protective Genetic Variants for Alzheimer Disease in the Amish - RENEWAL

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $1,573,916

## Abstract

Alzheimer disease (AD) is a devastating neurodegenerative disorder that affects millions of individuals in the
U.S. It has so far resisted attempts to develop effective therapies despite numerous (failed) clinical trials based
on known targets, most identified over 20 years ago. While genomic research (e.g. the Alzheimer’s Disease
Sequencing Project; ADSP) has identified numerous additional risk loci, these results derive primarily from case-
control datasets. In contrast, cohorts designed to identify variants that may protect from AD, and those using
complementary study designs, are few. We used our extensive experience with the Amish communities in
Indiana and Ohio to establish a cohort of older individuals at high risk of developing AD but who are cognitively
unimpaired (CU). The Amish provide a unique opportunity to identify protective variants for AD because of their
reduced background genetic variation and environmental risk factors. Their small founding population and
endogamy provides enrichment for rare variants. Founder populations also enable testing for non-additive allelic
effects and can magnify sub-significant association signals identified in case-control studies. The stability and
engagement of our Amish participants enables longitudinal assessments of cognition and biomarkers. Our
primary goals are to identify AD protective loci and characterize pre-clinical biomarkers of progression to
cognitive impairment. Building on our existing large cohort, our replicated protective locus and several suggestive
protective loci, and our existing biobank of DNA and plasma and databank of GWAS and WGS, we propose to:
1) Perform longitudinal assessment of cognition in our family-based Amish cohort; 2) Identify protective factors
for AD and predictors of progression to cognitive impairment by analyzing genomic and longitudinal cognitive,
biomarker, and SDOH data; and 3) Examine the functional implications of current and novel genes and variants
by prioritizing loci using in silico annotation for functional consequences followed by in vitro functional
characterization. Our results will identify potential druggable targets and accelerate the development of better
treatments for AD.

## Key facts

- **NIH application ID:** 10841016
- **Project number:** 5R01AG058066-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Jonathan L Haines
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,573,916
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841016

## Citation

> US National Institutes of Health, RePORTER application 10841016, Protective Genetic Variants for Alzheimer Disease in the Amish - RENEWAL (5R01AG058066-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841016. Licensed CC0.

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