NG00103 - Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease

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Description

Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. The objective of this study was to examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.

Genome-wide association studies of positron emission tomographic (PET) imaging amyloid levels, followed by a meta-analysis, were conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer’s Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. Participants older than 50 years with amyloid PET imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3,154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1,160) provided additional amyloid PET imaging data with existing genetic data.

Available Filesets

Name	Accession	Latest Release	Description
Amyloid PET: Full summary statistics (application needed)	fsa000098	NG00103.v1	Full summary statistics
Amyloid PET: P-values only (open access)	fsa000099	NG00103.v1	P-values only

View the File Manifest for a full list of files released in this dataset.

Consent Level	Number of Subjects
DS-ADRD-IRB-PUB-NPU	NA

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

Use the study-specific acknowledgement statements below (as applicable):

For investigators using any data from this dataset:

Please cite/reference the use of NIAGADS data by including the accession NG00103.

For investigators using Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease (sa000047) data:

This research was supported in part by NIA grants RF1-AG054023, K01-AG049164, R01-AG059716, R21-AG059941, HHSN311201600276P, K24-AG046373, R01-AG034962, R01-NS100980, P30AG10161, R01AG15819, R01AG17917, R01-AG056534, R01AG036836, R01AG034570, R01-AG063689, U19-AG010483, U01-AG061356, U01-AG024904, P30-AG010133, R01-AG054047, and R01-AG019771; the Intramural Research Program of the NIA/NIH; the Vanderbilt Memory and Alzheimer's Center; and The Columbia University Alzheimer’s Disease Research Center grant P50-AG008702. The Vanderbilt Neurosciences Biospecimen Bank is supported by philanthropy from the Kirshner Research Fund. The Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) study is a secondary prevention trial in preclinical Alzheimer’s disease, aiming to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. The A4 Study is funded by a public-private-philanthropic partnership, including funding from the NIH/NIA, Eli Lilly and Co, Alzheimer’s Association, Accelerating Medicines Partnership, GHR Foundation, an anonymous foundation, and additional private donors, with in-kind support from Avid and Cogstate. The companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study is funded by the Alzheimer’s Association and GHR Foundation.

Total number of approved DARs: 1

Investigator:
Cruchaga, Carlos
Institution:
Washington University School of Medicine
Project Title:
The Familial Alzheimer Sequencing (FASe) Project
Date of Approval:
May 9, 2024
Request status:
Approved
Research use statements:
Show statements
Technical Research Use Statement:
The goal of this study is to identify new genes and mutations that cause or increase risk for Alzheimer disease (AD), as well as protective factors. Individuals and families were selected from the Knight-ADRC (Washington University) and the NIA-LOAD study. Only families with at least three first-degree affected individuals were included. Families with pathogenic variants in the known AD or FTD genes, or in which APOE4 segregated with disease were excluded. At least two cases and one control were selected per family. Cases had an age at onset (AAO) after 65 yo and controls had a larger age at last assessment than the latest AAO within the family. Whole exome (WES) and whole genome sequencing (WGS) was generated for 1,235 individuals (285 families) that together with data from our collaborators and the ADSP family-based cohort (3,449 individuals and 757 families) will provide enough statistical power to identify new genes for AD. Dr. Tanzi (Harvard Medical School) will provide WGS from 400 families from the NIMH Alzheimer disease genetics initiative study. We will perform single variant and gene-based analyses to identify genes and variants that increase risk for disease in AD families. Single variant analysis will consist of a combination of association and segregation analyses. We will run family-based gene-based methods to identify genes that show and overall enrichment of variants in AD cases. We will also look for protective and modifier variants. To do this we will identify families loaded with AD cases, that also include individuals with a high burden of known risk variants but that do not develop the disease (escapees). We will use the sequence data and the family structure to identify variants that segregate with the escapee phenotype. The most promising variants and genes will be replicated in independent datasets (ADSP case-control, ADNI, Knight-ADRC, NIA-LOAD ). We will perform single variant and gene-based analyses to replicate the initial findings, and survival analysis to replicate the protective variants. We will select the most promising variants/genes for functional studies
Non-Technical Research Use Statement:
Family-based approaches led to the identification of disease-causing Alzheimer’s Disease (AD) variants in the genes encoding APP, PSEN1 and PSEN2. The identification of these genes led to the A?-cascade hypothesis and to the development of drugs that target this pathway. Recently, we have identified rare coding variants in TREM2, ABCA7, PLD3 and SORL1 with large effect sizes for risk for AD, confirming that rare coding variants play a role in the etiology of AD. In this proposal, we will identify rare risk and protective alleles using sequence data from families densely affected by AD. We hypothesize that these families are enriched for genetic risk factors. We already have sequence data from 695 families (2,462 individuals), that combined with the ADSP and the NIMH dataset will lead to a dataset of more than 1,042 families (4,684 individuals). Our preliminary results support the flexibility of this approach and strongly suggest that protective and risk variants with large effect size will be found, which will lead to a better understanding of the biology of the disease.

NG00103 – Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease

Overview

Description

Available Filesets

Related Studies

Consent Levels

Acknowledgement

Acknowledgment statement for any data distributed by NIAGADS:

For investigators using any data from this dataset:

For investigators using Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease (sa000047) data:

Related Publications

Approved Users

Total number of samples: 0