# Genetic Architecture of Alzheimer’s disease Proteinopathies

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $2,243,331

## Abstract

Project Summary/Abstract
In order to enhance and focus research on Alzheimer's disease (AD)-specific proteinopathies, the 2018
research framework proposed by the National Institute on Aging and Alzheimer's Association (NIA-AA)
recommends that AD be defined by its specific biological signatures that can be documented at autopsy or in
living people by biomarkers rather than by its non-specific neurodegenerative and clinical syndromic features.
Of the three proposed biomarkers by the NIA-AA research framework in living people (amyloid-beta (Aβ),
pathologic tau and neurodegeneration), only the two AD-specific proteinopathies (Aβ and pathologic tau) are
considered obligatory for the biological definition of AD, while neurodegeneration, although contribute to
cognitive impairment and is part of the fully manifested disease, can also occur in other brain disorders and
thus is not specific to AD. The purpose of this harmonized biological definition of AD in living people that
includes the preclinical phase is to distinguish AD from other types of brain disorders and dementia, to
accelerate and focus research on AD-specific proteinopathies that manifest decades before the clinical
manifestation of first symptoms of AD, to enhance better understanding in the underlying mechanisms of AD
clinical expression, and to use (and discover) targeted disease modifying interventions that can prevent or
delay the onset of AD symptoms.
Our ongoing and long-term research interest coincides well with the NIA-AA research framework in living
people where we have already performed genome-wide association studies (GWAS) on CSF Aβ42/tau levels
and Aβ deposition in the brain measured by amyloid-PET and identified known and novel associations in the
APOE and non-APOE regions. However, the identified signals do not explain all of the phenotypic variation in
the two AD-specific proteinopathies or endophenotypes. Here we propose a collaborative study between
leading experts in the field to extend our ongoing efforts to delineate the complete genetic basis of the two AD-
specific proteinopathies (Aβ and pathologic tau) by whole genome sequencing (WGS) using well-characterized
and large amyloid-PET and CSF Aβ42/tau datasets with clinical outcomes of dementia followed by testing the
effects of identified significant variants on downstream neurodegeneration markers, and performing extensive
bioinformatics and functional studies. The primary objective of this application is to perform and analyze WGS
in adequately powered large discovery samples with well-characterized Aβ and tau data along with clinical
outcomes of dementia to identify putative functional variants associated with Aβ and tau pathologies followed
by replications in independent and large samples with Aβ and tau data (Aims 1-2). We will integrate genetic
information to create polygenic risk scores in order to predict Aβ and tau pathologies and will also examine the
role of AD pathology-associated variants with downstream ...

## Key facts

- **NIH application ID:** 9995650
- **Project number:** 1R01AG064877-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Carlos Cruchaga
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,243,331
- **Award type:** 1
- **Project period:** 2021-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995650

## Citation

> US National Institutes of Health, RePORTER application 9995650, Genetic Architecture of Alzheimer’s disease Proteinopathies (1R01AG064877-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9995650. Licensed CC0.

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