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Meta-Analysis
. 2020 Oct 1;77(10):1288-1298.
doi: 10.1001/jamaneurol.2020.1760.

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

Neha S Raghavan  1   2   3   4 , Logan Dumitrescu  5   6 , Elizabeth Mormino  7 , Emily R Mahoney  5   6 , Annie J Lee  1   2   3 , Yizhe Gao  1   2   3 , Murat Bilgel  8 , David Goldstein  1   2   3 , Theresa Harrison  9 , Corinne D Engelman  10 , Andrew J Saykin  11   12 , Christopher D Whelan  13 , Jimmy Z Liu  13 , William Jagust  9 , Marilyn Albert  14 , Sterling C Johnson  15 , Hyun-Sik Yang  16   17 , Keith Johnson  16   17 , Paul Aisen  18 , Susan M Resnick  8 , Reisa Sperling  16   17 , Philip L De Jager  1   2   3   19   20 , Julie Schneider  21 , David A Bennett  21 , Matthew Schrag  5 , Badri Vardarajan  1   2   3   4 , Timothy J Hohman  5   6 , Richard Mayeux  1   2   3   4 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations
Meta-Analysis

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

Neha S Raghavan et al. JAMA Neurol. .

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 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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mormino reported receiving funding from National Institutes of Health (NIH) grant K01AG051718 during the conduct of the study, personal fees from Roche, and grants from the NIH outside the submitted work. Dr Goldstein reported other support from Q State-Pairnomix, other support from Praxis Therapeutics, other support from Apostle Inc, and personal fees from AstraZeneca, Gilead Sciences, and GoldFinch Bio outside the submitted work. Dr Engelman reported receiving grants from the NIH during the conduct of the study. Dr Saykin reported receiving grants from the NIH during the conduct of the study; other support from Springer-Nature outside the submitted work, and F18-flortaucipir precursor as in-kind support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly. Dr Whelan reported other support from Biogen during the conduct of the study and is an employee of Biogen. Dr Albert reported receiving grants from the National Institute on Aging (NIA) during the conduct of the study and is a consultant for Eli Lilly. Dr S. C. Johnson reported receiving grants from the NIH during the conduct of the study, personal fees from Roche Diagnostics, and grants and nonfinancial support from Cerveau Technologies outside the submitted work. Dr Aisen reported receiving grants from Eli Lilly and the NIH during the conduct of the study, as well as personal fees from Merck, Roche, Biogen, ImmunoBrain Checkpoint, and Samus outside the submitted work. Dr Sperling reported receiving grants from Eli Lilly and the Alzheimer's Association during the conduct of the study, as well as personal fees from AC Immune, Eisai, Roche, Neurocentria, and Takeda and grants from Janssen outside the submitted work. Dr Schneider reported receiving grants from the NIH during the conduct of the study. Dr Bennett reported receiving grants from the NIH and Illinois during the conduct of the study. Dr Schrag reported receiving grant K76AG060001 from the NIH/NIA and grant R03NS111486 from the NIH/National Institute of Neurological Disorders and Stroke during the conduct of the study, as well as grants from the NIH and a loan repayment grant outside the submitted work. Dr Hohman reported receiving grants from the NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association of 2 Single-Nucleotide Variants in the RBFOX1 Gene With Amyloid Levels
A, Genome-wide significance (α = 5 x 10−8), suggestive (α = 1 x 10−5). Gene symbols for suspected genes within locus. B, Regional plots of the RBFOX1 locus. Points are colored by linkage disequilibrium with the top variant, denoted by the diamond shape. C, Associations across studies. Squares (point estimate) 95% CIs (line segments); size inversely related to the variance. chr, chromosome; cM/Mb, megabase; PiB, Pittsburgh compound B; Other abbreviations are expanded in note to Table 1.
Figure 2.
Figure 2.. Microscopy of RBFOX1, Neuropil Threads, and Neurofibrillary Tangles
A, In postmortem control human brain tissue, RBFOX 1 (red) is localized to neurons (neurofilament, green). B, In Alzheimer disease brain, RBFOX1 localizes to neuropil threads around β-amyloid plaques (methoxy-X04, blue). C, In Alzheimer disease brain, RBFOX1 is present in tau tangles (arrowheads) and neuropil threads running through dystrophic neurites (cathepsin B, green) surrounding β-amyloid plaques (methoxy-X04, blue). Insets: cross-section through a dystrophic neurite showing lysosomes (green) surrounding a core of tau (blue) on which RBFOX1 (red) is enriched. Scale bar is 20 μm. Width of inset box is 12 μm.
See this image and copyright information in PMC

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