Elsevier

Neurobiology of Aging

Volume 101, May 2021, Pages 299.e13-299.e21
Neurobiology of Aging

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

https://doi.org/10.1016/j.neurobiolaging.2020.11.009Get rights and content

Highlights

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    8 loci in synapse-encoding genes can predict Alzheimer's disease with 72% accuracy.

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    This hypothesis-driven approach to polygenic risk improved upon current models.

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    Genetic variation in glutamate, APP and tau pathways contribute to pathogenesis.

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    This new model may be used to identify individuals at risk of Alzheimer's disease.

Abstract

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.

Section snippets

Background

The genetic component of early-onset familial Alzheimer's disease (AD) is attributed to genetic variants in the APP, PSEN1, and PSEN2 genes, all of which are central to the amyloid cascade hypothesis (Hardy and Selkoe, 2002). The most prominent late-onset AD (LOAD) risk locus (APOE) was detected almost 30 years ago (Pericak-Vance et al., 1991). The ε4 allele of APOE confers a 3-fold increased risk for AD in heterozygous carriers increasing to up to 12-fold in the homozygous state (Corder

Patient samples

Experimental procedures were approved by local ethics committees—Nottingham Research Ethics Committee 2 (REC reference 04/Q2404/130) and London – City and East NRES (REC reference 08/H0704/128+5) and completed in accordance with approved guidelines. All donors gave written informed consent as governed by local guidelines. The DNA samples used in this study were extracted from autopsied brain tissue prospectively selected from batch 1 and 2 (target data set) and batch 3 (validation data set)

Results

The BDR samples used in the target data set included 137 controls and 302 patients with pathologically confirmed LOAD. The mean age-at-death and male:female ratio were comparable between controls (83.7 years, standard deviation 9.9%, 48% female) and patients with LOAD (82.9 years, standard deviation 8.5, p = 0.4, 50% female, p = 0.8). As expected, the percentage of APOE ε4 carriers was higher in patients with LOAD (66%) than that in controls (16%, p < 0.001)..

The optimal threshold for inclusion

Discussion

Here, we report that a PRS based on 8 SNPs located in 6 genes that encode synaptic proteins shows improved (72.0%) predictive accuracy compared with the APOE locus (67.7%) in 137 controls and 302 patients with LOAD. Moreover, the synaptic PRS performed similarly to the previously reported NeuroChip PRS (69.3%), which includes the 8 SNPs that comprise the synaptic PRS or a proxy. The predictive accuracy of the synaptic PRS was replicated (73.1%) in a second, independent data set of 80 controls

Conclusions

The data reported here lend further support to the hypothesis that polygenic risk may account for some of the missing heritability in AD and that a pathway-targeted approach can result in PRS with high predictive accuracy for a relatively small number of variants. The relative simplicity of the synaptic PRS without a concomitant drop in predictive capacity supports the hypothesis that synapse-encoding genes are enriched for LOAD risk-modifying loci. While caution should be taken in interpreting

CRediT authorship contribution statement

Ted Lawingco: Formal analysis, Investigation, Writing - original draft. Sultan Chaudhury: Formal analysis, Investigation, Methodology, Writing - review & editing. Keeley J. Brookes: Formal analysis, Investigation, Methodology, Writing - review & editing. Tamar Guetta-Baranes: Formal analysis, Investigation, Writing - review & editing. Rita Guerreiro: Investigation, Resources, Writing - review & editing. Jose Bras: Investigation, Resources, Writing - review & editing. John Hardy: Investigation,

Acknowledgements

The authors gratefully acknowledge all the donors and their families for the tissue provided for this study. Human postmortem tissue was obtained from the South West Dementia Brain Bank, London Neurodegenerative Diseases Brain Bank, Manchester Brain Bank, Newcastle Brain Tissue Resource and Oxford Brain Bank, members of the Brains for Dementia Research (BDR) Network. The authors acknowledge the neuropathologists at each centre (the South West Dementia Brain Bank, the Manchester Brain Bank,

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    These authors contributed equally to this work.

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