Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Professor Alan ThomasORCiD


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


© 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.

Publication metadata

Author(s): Lawingco T, Chaudhury S, Brookes KJ, Guetta-Baranes T, Guerreiro R, Bras J, Hardy J, Francis P, Thomas A, Belbin O, Morgan K

Publication type: Article

Publication status: Published

Journal: Neurobiology of Aging

Year: 2021

Volume: 101

Pages: 299.e13-299.e21

Online publication date: 12/11/2020

Acceptance date: 07/11/2020

ISSN (print): 0197-4580

ISSN (electronic): 1558-1497

Publisher: Elsevier Inc.


DOI: 10.1016/j.neurobiolaging.2020.11.009

PubMed id: 33303219


Altmetrics provided by Altmetric


Funder referenceFunder name