# Personalized genetic profiles of risk and resilience in Alzheimer's and vascular diseases

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $724,986

## Abstract

Prior research and the 2018 NIA-Alzheimer’s-Association framework emphasize that novel insights into
the complex biology and heterogeneity of Alzheimer’s disease (AD) are needed to develop efficient
interventions that can be tailored to persons’ unique risk profiles. These profiles are likely a result of an
interplay of many genetic and non-genetic risk and protective factors for AD, including those of vascular
origin, which are difficult to disentangle. Emerging evidence suggests also that ADs and vascular
diseases tend to cluster together. This project addresses an objective of PAR-17-054 on disentangling
heterogeneous interactions of genetic and AD/vascular risk factors in risk and resilience to AD, including
age-specific effects, by leveraging existing resources and engaging in activities that will improve
statistical power. Our approach, combining thorough methods of genome-wide association studies and
the rigor of the candidate-like methods in large samples, is built on: (i) core principles of evolutionary
biology in genetics of AD and other age-related traits characteristic of post-reproductive life, which deals
with an inherent heterogeneity in genetic predisposition to such traits, (ii) insights from prior studies of
such traits (including our own work), and (iii) promising results of our large-scale studies proving its
significance, feasibility, and potential to substantially improve power using the existing resources. This
research contributed to better understanding of weaknesses in the rigor of prior studies and provided
compelling evidence that our approach is a natural and critical strategy to advance the progress in
dissecting the inherently heterogeneous mechanisms of AD and vascular traits. The goal is to identify
personalized (i.e., more homogeneous, group-specific) mono/polygenic profiles of risks and resilience
to AD and vascular diseases in the disease-specific and pleiotropic contexts in prioritized loci leveraging
information from the AD-centered pleiotropic meta-analysis planned in this project and previous
analyses by our and other research groups, and identify the role of AD risk and other factors in these
profiles. We will address the following specific aims: Aim 1. Identify specific and pleiotropic loci for AD
and vascular traits from new analyses and the existing studies. Aim 2. Dissect heterogeneity leveraging
the analysis of molecular signatures defined as differences in linkage disequilibrium structures in
affected and unaffected subjects. Aim 3. Identify personalized genetic profiles of AD-specific and
pleiotropic risks and resilience. Aim 4. Characterize the functional roles of SNPs from the identified
mono/polygenic variants and biological roles of genes for these SNPs. Characterize transcription
pathways for SNPs using individual-level gene expression and epigenetic data and summary statistics
from the available expression and methylation quantitative trait loci studies.

## Key facts

- **NIH application ID:** 10769801
- **Project number:** 5R01AG065477-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** ALEXANDER M KULMINSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $724,986
- **Award type:** 5
- **Project period:** 2020-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769801

## Citation

> US National Institutes of Health, RePORTER application 10769801, Personalized genetic profiles of risk and resilience in Alzheimer's and vascular diseases (5R01AG065477-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10769801. Licensed CC0.

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