# Immunogenetic contribution to the progression of preclinical Alzheimer's disease

> **NIH NIH K23** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $196,775

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD) is a devastating neurodegenerative disorder without an effective disease-modifying
treatment. The critical role of myeloid cell in the progression of AD is supported by genome-wide association
studies (GWAS) that show strong enrichment of myeloid cell gene variants in the genetic architecture of AD.
However, the specific contributions of the immunogenetic variations to the AD pathogenesis and progression
remain unknown. This is a particularly critical knowledge gap in preclinical AD, when an effective intervention
could still prevent widespread irreversible neurodegeneration. To achieve our long-term goal of to identify
therapeutic targets in preclinical AD by better understanding how immunogenetic AD risk variants affect
pathophysiology, the objective of this K23 project is to identify, in preclinical AD, specific AD-relevant
phenotypes that result from immunogenetic AD risk. Our central hypothesis is that higher immunogenetic AD
risk predicts higher AD pathology burden, alters myeloid cell gene expression, and causes faster
neurodegeneration and cognitive decline in preclinical AD. We will utilize use a specifically targeted polygenic
risk score to capture the aggregate immunogenetic AD risk, and investigate our hypothesis in large samples of
>4,000 clinically normal (CN) older adults from the Anti-Amyloid Treatment in Asymptomatic AD (A4)
Study/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) screening dataset and 270
CN older adults from the Harvard Aging Brain Study (HABS). We will test our hypotheses by determining the
contribution of immunogentic AD risk to (1) cross-sectional AD pathology (as estimated by amyloid/tau PET)
(A4/LEARN/HABS), (2) altered expression of myeloid cell gene co-expression modules (HABS), and (3)
longitudinal progression of tau pathology, neurodegeneration, and cognitive decline (HABS). During his K23
Patient-Oriented Research Career Development Award period, the candidate's short-term career goal is to
transition to an independent clinical investigator elucidating the clinical implications of the genetic architecture
of AD, with focus on immunogenetic contribution to the progression of preclinical AD. To achieve this goal, the
candidate plans to (1) gain expertise in the neuroimaging biomarkers of preclinical AD, (2) enhance
genomic/transcriptomic (“omics”) data production and analysis skills, and (3) continue his training in
biostatistics. By successfully executing the proposed project and training, the candidate will be in an ideal
position to emerge as an independent NIH-funded clinical investigator, and achieve the long-term career goal
of leading a collaborative research program to translate advances in omics into personalized prognostication
and therapeutic target identification in AD. The candidate is fortunate to be in an ideal environment for his
research project and training, with access to exceptional resources and research community ...

## Key facts

- **NIH application ID:** 10105253
- **Project number:** 5K23AG062750-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Hyun-Sik Yang
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $196,775
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105253

## Citation

> US National Institutes of Health, RePORTER application 10105253, Immunogenetic contribution to the progression of preclinical Alzheimer's disease (5K23AG062750-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105253. Licensed CC0.

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