# Alzheimer Disease Genetic Architecture in African Americans

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $813,421

## Abstract

ABSTRACT
A portion of the genetic component of Alzheimer disease (AD) is explained by genes identified by positional
cloning, targeted gene analysis, GWAS and next generation sequencing approaches. With few notable
exceptions, the functional variants in these genes and precise pathogenic mechanisms by which these variants
lead to AD are unknown. We will continue to direct our efforts on persons of African ancestry (AA), a group
with a high incidence of dementia but studied much less than persons of European ancestry (EA). We will
leverage rich AD-related endophenotype and other risk factor data from the largest collection of AAs
assembled by us, the Alzheimer Disease Genetics Consortium (ADGC) and Alzheimer Disease Sequencing
Project (ADSP) for genetic studies of AD to promote further discovery of AD-related genes and variants as well
as their mechanisms of action leading to AD. Previously, we demonstrated significant association of AD with
SORL1, AKAP9, and other genes in AAs using standard and novel analytic approaches. In the next project
period, we will perform RNA sequencing on brain tissue obtained from more than 140 AA AD cases and
controls, and analyze these data using state-of-the-art bioinformatics approaches to assess the influence of AD
risk variants on gene expression. We will construct AA-specific Bayesian elastic-net models of genetically-
mediated gene expression using the AA brain cohort genotype and RNAseq data. These models will be
applied to AA cohorts from the ADGC and ADSP (total n=9,200) using PrediXcan to construct AA-specific
expression predictions In addition, we will identify non-genetic mediators of genetic influences on AD risk by (1)
performing gene ˣ environment GWASs of AD in AAs using data for several established AD risk factors using
data from the ADGC/ADSP, UK Biobank and Million Veterans Program; (2) applying mendelian randomization
to assess the causal relationship between diabetes, cigarette smoking, hypertension, hypercholesterolemia,
obesity and AD in AAs using existing GWAS summary statistics for these traits in AAs; and (3) conducting a
phenome-wide association study (PheWAS) to identify pleiotropy by deriving a polygenic risk score for AD in
AAs and testing its association with a range of phenotypes within the UK Biobank. We will also perform in vitro
experiments (including knockdown by siRNA, gene and protein over-expression, immunofluorescence, and
ELISA) in human neuronal cells and induced pluripotent stem cell-derived neurons containing AA AD risk
variants inserted by CRISPR to understand how genetic variation in AKAP9 and other promising genes leads
to AD-related pathologic states as well as to provide models that can be used in small molecule drug screens
for potential AD treatments.

## Key facts

- **NIH application ID:** 9973631
- **Project number:** 2R01AG048927-06
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Lindsay A. Farrer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $813,421
- **Award type:** 2
- **Project period:** 2015-02-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973631

## Citation

> US National Institutes of Health, RePORTER application 9973631, Alzheimer Disease Genetic Architecture in African Americans (2R01AG048927-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973631. Licensed CC0.

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