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Uncovering exactly how RBFOX1 regulates amyloid plaque could lead to ways to prevent plaque accumulation. Image is in the public domain.

New gene may drive earliest brain changes in Alzheimer’s

Summary: Genetic analysis of almost 4,300 samples reveals a link between the appearance of amyloid deposits, APOE, and a novel gene called RBFOX1. Lower levels of RBFOX1 in the brain appear to be associated with increased amyloid and global cognitive decline over a person’s lifetime.

Source: Columbia University

A newly discovered Alzheimer’s gene may drive the first appearance of amyloid plaques in the brain, according to a study led by researchers at Columbia University Irving Medical Center.

Some variants of the gene, RBFOX1, appear to increase the concentration of protein fragments that make up these plaques and may contribute to the breakdown of critical connections between neurons, another early sign of the disease.

The finding could lead to new therapies that prevent Alzheimer’s and better ways of identifying people with the greatest risk of developing the disease.

Background

In recent years, amyloid PET brain imaging has helped to reveal that the earliest signs of Alzheimer’s disease — deposits of amyloid in the brain – appear as early as 10 or 15 years before any symptoms of the disease become apparent.

But aside from the few cases caused by rare, inherited genes, researchers have been searching for the cause of excessive accumulation of amyloid in the brain of Alzheimer’s patients.

To find genes that drive EARLY amyloid accumulation, the new study examined the genomes of thousands of people whose PET images revealed amyloid deposits in the brain but who had not yet developed Alzheimer’s symptoms.

“By studying people with the earliest signs of Alzheimer’s, we can find genes that are unequivocally related to the start of disease. And these genes are more likely to lead to therapies that can prevent the disease from developing,” says Richard Mayeux, MD, chair of neurology at Columbia University Vagelos College of Physicians and Surgeons, who led the study.

What’s New

The study looked through the genomes of nearly 4,300 people who did not have Alzheimer’s but whose brains already contained variable amounts of amyloid plaque, as measured by PET imaging using amyloid tracers.

A genetic analysis uncovered a link between the appearance of amyloid deposits and APOE, a known Alzheimer’s gene, and a novel gene, RBFOX1.

About 10% of people in the study (predominantly with European ancestry) had RBFOX1 variants that were linked with the emergence of amyloid deposition.

Lower amounts of RBFOX1 in the brain appeared to be associated with increased amyloid and global cognitive decline during life.

Why It Matters

Uncovering exactly how RBFOX1 regulates amyloid plaque could lead to ways to prevent plaque accumulation. Previous research has already suggested RBFOX1 is involved in the formation of amyloid precursors and the breakdown of synapses between neurons.

The connection between RBFOX1 and amyloid plaques may be relatively easy to untangle, unlike the well-known connection between APOE4 and amyloid, which is still not understood after decades of research.

“I think we’re going to find that these markers of eventual disease are where real progress can be made against Alzheimer’s,” Mayeux says. “It will be virtually impossible to change the disease course at the time symptoms appear. By then, the disease has already flourished for 10 to 15 years.”

“If we can target the genes that get amyloid started — and correct those problems somehow — we may be able to prevent the disease.”

Additional authors: Neha S. Raghavan (Columbia University Irving Medical Center); Logan Dumitrescu (Vanderbilt University); Elizabeth Mormino (Stanford University); Emily R. Mahoney (Vanderbilt); Annie J. Lee (CUIMC); Yizhe Gao (CUIMC); Murat Bilgel (National Institute on Aging, NIH); David Goldstein (CUIMC); Theresa Harrison (University of California, Berkeley); Corinne D. Engelman (University of Wisconsin); Andrew J. Saykin (Indiana University); Christopher D. Whelan (Biogen); Jimmy Z. Liu (Biogen); William Jagust (University of California, Berkeley); Marilyn Albert (Johns Hopkins University); Sterling C. Johnson (University of Wisconsin); Hyun-Sik Yang and Keith Johnson (Massachusetts General and Brigham and Women’s Hospitals); Paul Aisen (University of Southern California); Susan M. Resnick (NIA); Reisa Sperling (Massachusetts General and Brigham and Women’s Hospitals); Philip L. De Jager, (CUIMC); Julie Schneider and David A. Bennett (Rush University Medical Center); Matthew Schrag (Vanderbilt University Medical Center); Badri Vardarajan, PhD (CUIMC); and Timothy J. Hohman (Vanderbilt University Medical Center).

Funding: This research was supported in part by grants from the NIH (RF1-AG054023, K01-AG049164, R01-AG059716, R21-AG059941, HHSN311201600276P, K24-AG046373, R01-AG034962, R01-NS100980, P30-AG10161, R01-AG15819, R01-AG17917, 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; the Vanderbilt Memory and Alzheimer’s Center; and The Columbia University Alzheimer’s Disease Research Center (NIH grant P50-AG008702).

About this neuroscience research article

Source:
Columbia University
Media Contacts:
Helen Garey – Columbia University
Image Source:
The image is in the public domain.

Original Research: Closed access
“Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease”. by Mayeux et al.
JAMA Neurology DOI

Abstract

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

Importance
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.

Objective
To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.

Design, Setting, and Participants
In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: 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. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), 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 = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020.

Main Outcomes and Measures
A genome-wide association study of PET imaging amyloid levels.

Results
From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10−9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = −0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort.

Conclusions and Relevance

RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.

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