Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2018 Mar 1;75(3):328-341.
doi: 10.1001/jamaneurol.2017.4198.

Associations of the Top 20 Alzheimer Disease Risk Variants With Brain Amyloidosis

Liana G Apostolova  1   2   3 , Shannon L Risacher  2 , Tugce Duran  1 , Eddie C Stage  1 , Naira Goukasian  4 , John D West  2 , Triet M Do  4 , Jonathan Grotts  5 , Holly Wilhalme  5 , Kwangsik Nho  2 , Meredith Phillips  1 , David Elashoff  5 , Andrew J Saykin  2   3 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations
Multicenter Study

Associations of the Top 20 Alzheimer Disease Risk Variants With Brain Amyloidosis

Liana G Apostolova et al. JAMA Neurol. .

Abstract

Importance: Late-onset Alzheimer disease (AD) is highly heritable. Genome-wide association studies have identified more than 20 AD risk genes. The precise mechanism through which many of these genes are associated with AD remains unknown.

Objective: To investigate the association of the top 20 AD risk variants with brain amyloidosis.

Design, setting, and participants: This study analyzed the genetic and florbetapir F 18 data from 322 cognitively normal control individuals, 496 individuals with mild cognitive impairment, and 159 individuals with AD dementia who had genome-wide association studies and 18F-florbetapir positron emission tomographic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective, observational, multisite tertiary center clinical and biomarker study. This ongoing study began in 2005.

Main outcomes and measures: The study tested the association of AD risk allele carrier status (exposure) with florbetapir mean standard uptake value ratio (outcome) using stepwise multivariable linear regression while controlling for age, sex, and apolipoprotein E ε4 genotype. The study also reports on an exploratory 3-dimensional stepwise regression model using an unbiased voxelwise approach in Statistical Parametric Mapping 8 with cluster and significance thresholds at 50 voxels and uncorrected P < .01.

Results: This study included 977 participants (mean [SD] age, 74 [7.5] years; 535 [54.8%] male and 442 [45.2%] female) from the ADNI-1, ADNI-2, and ADNI-Grand Opportunity. The adenosine triphosphate-binding cassette subfamily A member 7 (ABCA7) gene had the strongest association with amyloid deposition (χ2 = 8.38, false discovery rate-corrected P < .001), after apolioprotein E ε4. Significant associations were found between ABCA7 in the asymptomatic and early symptomatic disease stages, suggesting an association with rapid amyloid accumulation. The fermitin family homolog 2 (FERMT2) gene had a stage-dependent association with brain amyloidosis (FERMT2 × diagnosis χ2 = 3.53, false discovery rate-corrected P = .05), which was most pronounced in the mild cognitive impairment stage.

Conclusions and relevance: This study found an association of several AD risk variants with brain amyloidosis. The data also suggest that AD genes might differentially regulate AD pathologic findings across the disease stages.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Apostolova reported serving on an advisory board for Eli Lilly and Company and on the speaker’s bureau for Piramal and Eli Lilly and Company and receiving research support from GE Healthcare. Dr Saykin reported receiving research support from Eli Lilly and Company and AVID Radiopharmaceuticals. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association of Alzheimer Disease Risk Genes With Brain Amyloidosis in the Pooled Sample
Images were visualized using P < .01 (uncorrected) and cluster size (k) of 50 voxels. Scale indicates T values.
Figure 2.
Figure 2.. Association of Alzheimer Disease Risk Genes With Brain Amyloidosis in the Normal Control, Mild Cognitive Impairment, and Dementia Groups
Images were visualized using P < .01 (uncorrected) and cluster size (k) of 50 voxels. Scale indicates T values.
Figure 3.
Figure 3.. β-Coefficient Maps of the Main Association of FERMT2 and Its Interaction With Diagnosis and the Association of FERMT2 Within Each Diagnostic Group
Main association of FERMT2 with brain amyloidosis (A), its interaction with diagnosis (B), and the association of FERMT2 with brain amyloidosis in each diagnostic group (C) displayed using Statistical Parametric Mapping 8.
See this image and copyright information in PMC

Comment in

References

    1. Wingo TS, Lah JJ, Levey AI, Cutler DJ. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol. 2012;69(1):59-64. - PMC - PubMed
    1. Sleegers K, Lambert JC, Bertram L, Cruts M, Amouyel P, Van Broeckhoven C. The pursuit of susceptibility genes for Alzheimer’s disease: progress and prospects. Trends Genet. 2010;26(2):84-93. - PubMed
    1. Riddell DR, Zhou H, Atchison K, et al. . Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci. 2008;28(45):11445-11453. - PMC - PubMed
    1. Deane R, Sagare A, Hamm K, et al. . apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118(12):4002-4013. - PMC - PubMed
    1. Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287-303. - PMC - PubMed

Publication types

MeSH terms