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. The objective of this study was to examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.

Genome-wide association studies of positron emission tomographic (PET) imaging amyloid levels, followed by a meta-analysis, were conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals: 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. Participants older than 50 years with amyloid 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.

Timothy J. Hohman

Richard P. Mayeux

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

For investigators using Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease data:

This research was supported in part by NIA grants RF1-AG054023, K01-AG049164, R01-AG059716, R21-AG059941, HHSN311201600276P, K24-AG046373, R01-AG034962, R01-NS100980, P30AG10161, R01AG15819, R01AG17917, 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/NIH; the Vanderbilt Memory and Alzheimer's Center; and The Columbia University Alzheimer’s Disease Research Center grant P50-AG008702. The Vanderbilt Neurosciences Biospecimen Bank is supported by philanthropy from the Kirshner Research Fund. The Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) study is a secondary prevention trial in preclinical Alzheimer’s disease, aiming to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. The A4 Study is funded by a public-private-philanthropic partnership, including funding from the NIH/NIA, Eli Lilly and Co, Alzheimer’s Association, Accelerating Medicines Partnership, GHR Foundation, an anonymous foundation, and additional private donors, with in-kind support from Avid and Cogstate. The companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study is funded by the Alzheimer’s Association and GHR Foundation.

Raghavan NS, et al. Alzheimer’s Disease Neuroimaging Initiative. Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease. JAMA Neurol. 2020 Oct 1;77(10):1288-1298. doi: 10.1001/jamaneurol.2020.1760. PMID: 32568366; PMCID: PMC7309575. PubMed link