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

Kiddle SJ, Steves CJ, Mehta M, Simmons A, Xu X, Newhouse S, Sattlecker M, Ashton NJ, Bazenet C, Killick R, Adnan J, Westman E, Nelson S, Soininen H, Kloszewska I, Mecocci P, Tsolaki M, Vellas B, Curtis C, Breen G, Williams SC, Lovestone S, Spector TD, Dobson RJ - Transl Psychiatry (2015)

Bottom Line: Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34).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.

View Article: PubMed Central - PubMed

Affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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.

No MeSH data available.


Related in: MedlinePlus

The association between plasma MAP2K4 levels and (a) left parahippocampal volume in TwinsUK or (b) left entorhinal cortex volume in ANM. Scatterplot comparing plasma MAP2K4 levels with the volume of the left entorhinal cortex are given for the two cohorts. Points are coloured by APOE E4 data and whether they appear to be outliers. (a) GEEs covarying for age and taking into account twin relatedness show a suggestive association (Q<0.1) between plasma MAP2K4 and the volume of the left entorhinal cortex in TwinsUK. (b) Linear regression covarying for age and centre shows a suggestive association (Q<0.1) between plasma MAP2K4 and the volume of the left entorhinal cortex in ANM, when a possible outlier (in blue) is included (β=−0.64, P=0.0025 and Q=0.088), or nominal association (P<0.05) when it is excluded (β=−0.54 and P=0.014). ANM, AddNeuroMed; GEE, generalised estimation equation.
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fig2: The association between plasma MAP2K4 levels and (a) left parahippocampal volume in TwinsUK or (b) left entorhinal cortex volume in ANM. Scatterplot comparing plasma MAP2K4 levels with the volume of the left entorhinal cortex are given for the two cohorts. Points are coloured by APOE E4 data and whether they appear to be outliers. (a) GEEs covarying for age and taking into account twin relatedness show a suggestive association (Q<0.1) between plasma MAP2K4 and the volume of the left entorhinal cortex in TwinsUK. (b) Linear regression covarying for age and centre shows a suggestive association (Q<0.1) between plasma MAP2K4 and the volume of the left entorhinal cortex in ANM, when a possible outlier (in blue) is included (β=−0.64, P=0.0025 and Q=0.088), or nominal association (P<0.05) when it is excluded (β=−0.54 and P=0.014). ANM, AddNeuroMed; GEE, generalised estimation equation.

Mentions: Full results are given in Supplementary Tables 8–11. The plasma level of one protein—FAM107B—was found to associate with the volume of both the LE (β=1.05, Q=0.034) and RE (β=0.77, Q=0.015) cortices. Two proteins associated with the volume of one region (Q<0.05) were also associated with the volume of three out of four regions at a suggestive threshold of Q<0.1, NSF1C (positively with left hippocampus, LE and RE) and MAP2K4 (negatively with right hippocampus, LE and RE; Supplementary Tables 8–11). The association between MAP2K4 and LE cortex volume in TwinsUK is shown in Figure 2a.


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

Kiddle SJ, Steves CJ, Mehta M, Simmons A, Xu X, Newhouse S, Sattlecker M, Ashton NJ, Bazenet C, Killick R, Adnan J, Westman E, Nelson S, Soininen H, Kloszewska I, Mecocci P, Tsolaki M, Vellas B, Curtis C, Breen G, Williams SC, Lovestone S, Spector TD, Dobson RJ - Transl Psychiatry (2015)

The association between plasma MAP2K4 levels and (a) left parahippocampal volume in TwinsUK or (b) left entorhinal cortex volume in ANM. Scatterplot comparing plasma MAP2K4 levels with the volume of the left entorhinal cortex are given for the two cohorts. Points are coloured by APOE E4 data and whether they appear to be outliers. (a) GEEs covarying for age and taking into account twin relatedness show a suggestive association (Q<0.1) between plasma MAP2K4 and the volume of the left entorhinal cortex in TwinsUK. (b) Linear regression covarying for age and centre shows a suggestive association (Q<0.1) between plasma MAP2K4 and the volume of the left entorhinal cortex in ANM, when a possible outlier (in blue) is included (β=−0.64, P=0.0025 and Q=0.088), or nominal association (P<0.05) when it is excluded (β=−0.54 and P=0.014). ANM, AddNeuroMed; GEE, generalised estimation equation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490288&req=5

fig2: The association between plasma MAP2K4 levels and (a) left parahippocampal volume in TwinsUK or (b) left entorhinal cortex volume in ANM. Scatterplot comparing plasma MAP2K4 levels with the volume of the left entorhinal cortex are given for the two cohorts. Points are coloured by APOE E4 data and whether they appear to be outliers. (a) GEEs covarying for age and taking into account twin relatedness show a suggestive association (Q<0.1) between plasma MAP2K4 and the volume of the left entorhinal cortex in TwinsUK. (b) Linear regression covarying for age and centre shows a suggestive association (Q<0.1) between plasma MAP2K4 and the volume of the left entorhinal cortex in ANM, when a possible outlier (in blue) is included (β=−0.64, P=0.0025 and Q=0.088), or nominal association (P<0.05) when it is excluded (β=−0.54 and P=0.014). ANM, AddNeuroMed; GEE, generalised estimation equation.
Mentions: Full results are given in Supplementary Tables 8–11. The plasma level of one protein—FAM107B—was found to associate with the volume of both the LE (β=1.05, Q=0.034) and RE (β=0.77, Q=0.015) cortices. Two proteins associated with the volume of one region (Q<0.05) were also associated with the volume of three out of four regions at a suggestive threshold of Q<0.1, NSF1C (positively with left hippocampus, LE and RE) and MAP2K4 (negatively with right hippocampus, LE and RE; Supplementary Tables 8–11). The association between MAP2K4 and LE cortex volume in TwinsUK is shown in Figure 2a.

Bottom Line: Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34).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.

View Article: PubMed Central - PubMed

Affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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.

No MeSH data available.


Related in: MedlinePlus