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

Neha S. Raghavan, Logan Dumitrescu, Elizabeth Mormino, Emily R. Mahoney, Annie J. Lee, Yizhe Gao, Murat Bilgel, David Goldstein, Theresa Harrison, Corinne D. Engelman, Andrew J. Saykin, Christopher D. Whelan, Jimmy Z. Liu, William Jagust, Marilyn Albert, Sterling C. Johnson, Hyun Sik Yang, Keith Johnson, Paul Aisen, Susan M. ResnickReisa Sperling, Philip L. De Jager, Julie Schneider, David A. Bennett, Matthew Schrag, Badri Vardarajan, Timothy J. Hohman, Richard Mayeux

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1288-1298
Number of pages11
JournalJAMA Neurology
Volume77
Issue number10
DOIs
StatePublished - Oct 2020

ASJC Scopus subject areas

  • Clinical Neurology

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