# Protective Genetic Varients for Alzheimer Disease in the Amish

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $79,998

## Abstract

PROJECT SUMMARY (from the parent grant 5R01AG058066)
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:** 11081365
- **Project number:** 3R01AG058066-04S1
- **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:** $79,998
- **Award type:** 3
- **Project period:** 2022-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11081365

## Citation

> US National Institutes of Health, RePORTER application 11081365, Protective Genetic Varients for Alzheimer Disease in the Amish (3R01AG058066-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11081365. Licensed CC0.

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