RNA-Binding Protein RBFOX1 May Be Locus for Alzheimer’s Disease Pathogenesis

1. Lower RBFOX1 was associated with greater amyloid burden in the prefrontal cortex.

2. Reduced RBFOX1 was associated with increased rate of decline and reduced neurocognitive performance, and may be a novel locus for preclinical and early Alzheimer’s disease.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Genome-wide association studies (GWAS) have identified greater than 25 loci associated with Alzheimer’s disease (AD) development and progression, and are essential for the ongoing characterization and identification of therapeutic targets for the disease. In addition to inflicting significant mortality and morbidity, AD is characterized by a heterogeneous and preclinical phase of amyloid deposition that is difficult to analyze once a clinical diagnosis has been made. In combination with genetic studies tending to investigate later stages of the disease, has led to a significant knowledge gap about the genetic basis of the preclinical phase of AD.

This GWAS analyzed genetic and positron emission tomography (PET) imaging data from participants of several cohort studies that focused on older healthy adults. The study aimed to determine whether RBFOX1, an RNA-binding protein, was associated with brain amyloidosis in preclinical and early AD. Results suggested that RBFOX1 may be a novel locus involved in the pathogenesis of Alzheimer’s disease due to its effects on cognition and amyloid-β (Aβ). Study limitations included overrepresentation of white participants with high levels of education, as well as clinical heterogeneity across the studies utilized in analyses. Future studies should focus on intentional recruitment of people of color to ensure that other at-risk groups are adequately studied. Nonetheless, this study provides new evidence suggesting that RBFOX1 plays a role in neuronal development and may be a novel locus of brain amyloidosis and AD pathogenesis that can be assessed via PET imaging in preclinical and early stages.

Click to read the study in JAMA Neurology

Relevant Reading: Genome-Wide Association Study Identifies RBFOX1 Locus Influencing Brain Glucose Metabolism

In-Depth [prospective cohort]:

This GWAS began with a meta-analysis of six longitudinal cohort studies (n = 1,160) and six multicenter cohort studies (n = 3,154) of healthy older adults with genetic data between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study), Alzheimer Disease Neuroimaging Initiative, Baltimore Longitudinal Study of Aging, Berkeley Aging Cohort Study, Biomarkers of Cognitive Decline Among Normal Individuals cohort, and Wisconsin Registry for Alzheimer’s Prevention. Harmonization of amyloid data was then performed using a gaussian mixture model. A bimodal distribution was noted that separated amyloid-positive and -negative groups.

A total of 4,314 participants were included in the analysis (age range 52 to 96 years, 57% female). A strong association was noted between APOE and brain amyloidosis (single-nucleotide variant [SNV]: rs6857, β = 1.67, p = 5.79×10^-132). Further, a novel risk locus was discovered on chromosome 16p.13.3 that included RBFOX1 (SNV: rs56081887, β = 0.61, p = 3×10^-9). Increased amyloid levels were associated with RBFOX1 variants across all datasets except for Hispanic participants of the A4 Study.

RNA sequencing was conducted on autopsy data from the longitudinal Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). Reduced RBFOX1 messenger RNA (mRNA) levels within the prefrontal cortex of the 600 total participants was associated with greater Aβ burden (β = 0.008, p = 0.002) irrespective of cell type composition. Reduced RBFOX1 mRNA was further associated with increased rate of decline across all visits (β = 0.001, p = 4×10^-5) and reduced neurocognitive performance during participants’ final visits (β = 0.007, p = 0.006). In fact, RBFOX1 expression accounted for 1.5% of the variance in neurocognitive trajectories and remained significant when covarying for tau and amyloid, explaining 15% and 5% of the variance in neurocognitive trajectories, respectively. A one standard deviation decline in RBFOX1 was associated with an annual 0.2-point decrease in Mini-Mental Status Examination score.

Image: PD

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