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Genetic variants in glutamate-, A??, and tau-related pathways determine polygenic risk for Alzheimer's disease

Lawingco, Ted; Chaudhury, Sultan; Brookes, Keeley J.; Guetta-Baranes, Tamar; Guerreiro, Rita; Bras, Jose; Hardy, John; Francis, Paul; Thomas, Alan; Belbin, Olivia; Morgan, Kevin

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Ted Lawingco

Sultan Chaudhury

Keeley J. Brookes

Tamar Guetta-Baranes

Rita Guerreiro

Jose Bras

John Hardy

Paul Francis

Alan Thomas

Olivia Belbin

Kevin Morgan


© 2020 Elsevier Inc. Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the “synaptic PRS” in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%–6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset.


Lawingco, T., Chaudhury, S., Brookes, K. J., Guetta-Baranes, T., Guerreiro, R., Bras, J., …Morgan, K. (2021). Genetic variants in glutamate-, Aβ−, and tau-related pathways determine polygenic risk for Alzheimer's disease. Neurobiology of Aging, 101, 299.e13-299.e21.

Journal Article Type Article
Acceptance Date Nov 7, 2020
Online Publication Date Nov 12, 2020
Publication Date 2021-05
Deposit Date Nov 20, 2020
Publicly Available Date Nov 13, 2021
Journal Neurobiology of Aging
Print ISSN 0197-4580
Electronic ISSN 1558-1497
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 101
Pages 299.e13-299.e21
Keywords Polygenic risk score, Late-onset Alzheimer’s disease, Glutamate signaling, Aβ, Tau1
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