# Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $660,388

## Abstract

PROJECT SUMMARY
Genomic studies of Alzheimer's disease (AD) have primarily focused on non-Hispanic White (NHW) participants
affected by the late-onset form of the disease (LOAD; onset age: >65), or the study of early onset AD (EOAD;
onset age <=65) cases from families showing Mendelian inheritance patterns associated with mutations in the
APP, PSEN1 and PSEN2 genes. However, mutations in these three genes explain ~10% of EOAD cases. There
are no large-scale efforts to collect and study EOAD cases not explained by these genes, despite the fact that
this unexplained EOAD category accounts for ~90% of cases. The few smaller studies that have been conducted
suggest that the genetic architecture of EOAD overlaps with the late-onset form only partially. Thus, studying
EOAD in subjects without APP, PSEN1 and PSEN2 mutations is a critical gap that provides a unique opportunity
for discovering novel therapeutic targets and molecular pathways.
 To address this issue we aim to identify additional EOAD-associated variants through a large-scale whole-
genome sequencing (WGS) study of unexplained EOAD. We will include cases from several well-established
AD cohorts including the Resource for Early-onset Alzheimer Disease Research (READR), the Knight-ADRC at
Washington University, the Alzheimer's Disease Genetics Consortium (ADGC), and others. Generating and
harmonizing a dataset of 200 non-Hispanic White (NHW) and Caribbean Hispanic (CH) multiplex EOAD families,
over 4,000 EOAD singletons and over 13,000 unrelated, cognitive controls, all with WGS, this project will yield
the largest EOAD genomics dataset to-date, improving statistical power for variant identification and allowing us
to assess the impact of specific factors such as APOE genotype, vascular risk factors, and neuropsychiatric
comorbidities. The inclusion of a large set of CH families and singletons will allow the examination of EOAD risk
in a significantly understudied but fast-growing minority population. Analyses will comprise both linkage and
association-based approaches, analyses of polygenic and ancestry effects, and a thorough examination of
neurocognitive, neuropsychiatric and cardiovascular endophenotypes. We expect that when successfully
completed, this study will point to novel genetic contributors to EOAD, shed light on the mechanisms of AD and
facilitate the development of novel therapeutics.
 Sampling, phenotyping and sequencing analysis protocols will be complementary to and compatible with the
existing LOAD genomics resources, such as the Alzheimer Disease Sequencing Project (ADSP) and related
studies. This phenotypic and genomic consistency, together with the use of existing AD infrastructure
(NIAGADS), allows for immediate integration with the leading efforts on LOAD, enabling rapid large-scale
investigation of a variety of additional critical AD genomics hypotheses.

## Key facts

- **NIH application ID:** 10667461
- **Project number:** 5R01AG064614-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Gary Wayne Beecham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $660,388
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-04-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667461

## Citation

> US National Institutes of Health, RePORTER application 10667461, Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes (5R01AG064614-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10667461. Licensed CC0.

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