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

Abstract

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 PARTICIPANTSIn 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 MEASURESA genome-wide association study of PET imaging amyloid levels. RESULTSFrom 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.

Genetic variants and functional pathways associated with resilience to Alzheimer’s disease

“…The current approach focusing on amyloid− does have limitations in the high end of amyloid+, so it is possible that we are underestimating the extent of amyloidosis in late stage disease. That said, our head to head comparison previously showed very small differences across harmonization approaches when amyloid is an outcome, and they would be further attenuated in the current context when amyloid levels are leveraged as a linear predictor ( Raghavan et al , 2020 ). The final scaled score represents a z -score based on the predicted amyloid− distribution among cognitively unimpaired older adults.…”

“…Mean SUVRs were scaled and normalized using the mean and standard deviation estimated from the predicted amyloid-negative (amyloid−) Gaussian distribution. A more comprehensive assessment of this and alternative harmonization approaches was recently published by our group ( Raghavan et al , 2020 ), but we used the present approach because it makes the fewest assumptions about the data and was more robust to outliers than alternative approaches. One alternative that we investigated previously is using the predicted amyloid− and amyloid-positive (amyloid+) distribution to give more sensitivity in the high end of the amyloid+ range ( Raghavan et al , 2020 ).…”

“…A more comprehensive assessment of this and alternative harmonization approaches was recently published by our group ( Raghavan et al , 2020 ), but we used the present approach because it makes the fewest assumptions about the data and was more robust to outliers than alternative approaches. One alternative that we investigated previously is using the predicted amyloid− and amyloid-positive (amyloid+) distribution to give more sensitivity in the high end of the amyloid+ range ( Raghavan et al , 2020 ). The current approach focusing on amyloid− does have limitations in the high end of amyloid+, so it is possible that we are underestimating the extent of amyloidosis in late stage disease.…”

Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population

“…Therefore, detecting individuals with Aβ deposition is of utmost importance for the prevention and early treatment of AD [5]. Previous studies have evaluated the genetic basis of Aβ deposition using positron emission tomography (PET) imaging [6][7][8][9][10] and identified several novel Aβ associated genetic variants outside the APOE region from European ancestry [11]. However, as each ancestry has a distinct genetic background, replication of the novel genetic findings in different populations is challenging.…”

Sex-stratified single-cell RNA-Seq analysis identifies sex-specific and cell type-specific transcriptional responses in Alzheimer’s disease across two brain regions.

“…3a). Some of these globally shared genes include CLU 9,46 , HSPA1A 47 , RBFOX1 48 , and CST3 49 , which are relevant in AD progression. Clustering of samples by AD compared to control pseudo-bulk cell type-specific gene expression (Fig.…”