A genome-wide association study of plasma phosphorylated tau181

Plasma phosphorylated tau at threonine-181 (P-tau181) demonstrates promise as an accessible blood-based biomarker specific to Alzheimer's Disease (AD), with levels recently demonstrating high predictive accuracy for AD-relevant pathology. The genetic underpinnings of P-tau181 levels, however, remain elusive. This study presents the first genome-wide association study of plasma P-tau181 in a total sample of 1153 participants from 2 independent cohorts. No loci, other than those within the APOE genomic region (lead variant = rs429358, beta = 0.32, p =8.44 × 10-25) demonstrated association with P-tau181 at genome-wide significance (p < 5 × 10-08), though rs60872856 on chromosome 2 came close (beta = -0.28, p = 3.23 × 10-07, nearest gene=CYTIP). As the APOE ε4 allele is already a well-established genetic variant associated with AD, this study found no evidence of novel genetic associations relevant to plasma P-tau181, though presents rs60872856 on chromosome 2 as a candidate locus to be further evaluated in future larger size GWAS.


Introduction
Plasma phosphorylated tau181 (P-tau181) is a promising blood-based biomarker that is highly specific for Alzheimer's disease (AD) pathology. It correlates with cerebral A β and tau pathology , is specifically associated with AD neuropathology ( Lantero-  and predicts future cognitive decline ( Karikari et al., 2021 ). It therefore has great potential for the diagnostic and prognostic evaluation of AD. Identifying genetic loci associated with plasma P-tau181 could help enhance understanding of specific components of AD pathophysiology; in particular, tau-associated pathology. To date, 2 GWAS on AD-relevant CSF endophenotypes ( Cruchaga et al., 2013 ;  SNPs associated with P-tau181 at p < 5 × 10 −08 are in bold . Deming et al., 2017 ) have identified 5 loci, including APOE , to be associated with CSF P-tau181. Recently, we investigated the relation between AD polygenic risk scores (AD-PRS) and plasma P-tau181 ( Zettergren et al., 2021 ). No GWAS on plasma P-tau181 levels have yet, however, been performed. Here, we present the first plasma P-tau181 GWAS, aiming to identify genetic loci associated with plasma P-tau181 levels and in turn, tau-associated pathology.
To maximise sample power, ADNI and ANM were each analysed separately before combining into a fixed-effects meta-analysis with betas weighted by the inverse of their variance. Plasma P-tau181 data was log 10 transformed to approximate a normal distribution, and age, sex, and the first 7 PCs were controlled for within each study (Supplementary Methods). To correct for multiple testing, loci demonstrating evidence of an association at p < 5 × 10 −08 were considered to show evidence of an association with P-tau181.

Discussion
Here, we present the first GWAS of plasma P-tau181, in a sample of 1,153 individuals from ADNI and ANM. rs429358 within the APOE genomic region demonstrated evidence of a genomewide significant association with plasma P-tau181 (beta = 0.281, SE = 0.027, p = 2.54 × 10 −25 ). No other loci reached genomewide significance, though rs60872856 on chromosome 2 came close with a p-value of 3.23 × 10 −07 . This chromosome 2 variant is located nearest to the cytohesin-interacting protein CYTIP region, a region involved in the regulation of immune response. None of the SNPs previously associated with CSF P-tau181 levels ( Cruchaga et al., 2013 ;Deming et al., 2017 ) showed associations with plasma P-tau181 levels in this study.
The APOE ε4 allele is a well-established AD-associated genetic variant. Moreover, it has previously been shown to associate with AD-relevant pathology such as amyloid deposition, an event which is a precursor of elevated P-tau181 levels in the blood ( Karikari et al., 2021 ). This study therefore identifies no evidence of novel genetic associations relevant to plasma P-tau181. It does, however, present rs60872856 on chromosome 2 as a candidate which may show promise in future, well-powered GWAS (Supplementary Results). As blood P-tau181 is an easily accessible and scalable blood biomarker, large-scale GWAs studies exceeding those of CSF biomarkers will be soon feasible .

Disclosure statement
KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ has served at scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program.
AD Strategic Fund and the Alzheimer's Association ( #ADSF-21-831376-C , #ADSF-21-831381-C , and #ADSF-21-831377-C ), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden ( #FO2019-0228 ), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.neurobiolaging.2021. 04.015 .