Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes.

Steven J Kiddle ,Eric Westman ,Sally K Nelson ,Charles Curtis ,Chantal Bazenet ,Hilkka Soininen ,Magda Tsolaki ,Claire J Steves ,Mitul Mehta ,Jihad Adnan ,Stephen Newhouse ,Iwona Kłoszewska ,Xiaohui Xu ,Bruno Vellas ,Gerome Breen ,Steven Williams ,Nicholas J Ashton ,Patrizia Mecocci ,Richard Killick ,Simon Lovestone ,Tim D Spector ,Martina Sattlecker ,Andy Simmons ,Richard Dobson

doi:10.1038/tp.2015.78

Abstract

There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n=195), and regional brain volumes (n=34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q<0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD.

Highlights

No treatments exist that delay or prevent onset of Alzheimer’s disease (AD)
The median proportion of variance of plasma protein levels explained by additive genetics (A) was found to be 26% (IQR 3–46%)
The proportion explained by total familial factors (additive genetics (A) or twin-shared environment (C)) was 34% (IQR 3–74%)

Summary

Introduction

No treatments exist that delay or prevent onset of Alzheimer’s disease (AD). Studies using magnetic resonance imaging (MRI) and positron emission tomography brain scans have revealed early signs of AD pathology in subjects up to ~ 4 and ~ 17 years before the onset of dementia, respectively.[1]. Pathological changes are likely to be least advanced in asymptomatic subjects, and potentially the most remediable in this group. This is the motivation behind prevention trials in asymptomatic subjects with MRI or positron emission tomography evidence of early AD pathology.[2]. Such brain scans can be relatively expensive and require specialised facilities. Only two discovery studies have been performed comparing blood proteins to AD-related phenotypes exclusively in asymptomatic individuals.[6,7]

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