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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 relationship between plasma MAPKAPK5 levels and 10-year change in CANTAB-PAL in TwinsUK. Scatterplot comparing (a) plasma MAPKAPK5 levels and 10-year change in CANTAB-PAL in TwinsUK, or (b) MZ twin differences in both. Points are coloured by APOE E4 data. (a) GEEs covarying for age and taking into account twin relatedness show an association between plasma MAPKAPK5 and the 10-year change in CANTAB-PAL (β=0.48, Q=0.0059). (b) Linear regression covarying for age shows an association between plasma MAPKAPK5 and the 10-year change in CANTAB-PAL in the MZ twin difference context (β=0.55, P=0.030). CANTAB-PAL, CANTAB-paired associates learning; GEE, generalised estimation equation; MZ, monozygotic; RFU, relative fluorescence unit.
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fig1: The relationship between plasma MAPKAPK5 levels and 10-year change in CANTAB-PAL in TwinsUK. Scatterplot comparing (a) plasma MAPKAPK5 levels and 10-year change in CANTAB-PAL in TwinsUK, or (b) MZ twin differences in both. Points are coloured by APOE E4 data. (a) GEEs covarying for age and taking into account twin relatedness show an association between plasma MAPKAPK5 and the 10-year change in CANTAB-PAL (β=0.48, Q=0.0059). (b) Linear regression covarying for age shows an association between plasma MAPKAPK5 and the 10-year change in CANTAB-PAL in the MZ twin difference context (β=0.55, P=0.030). CANTAB-PAL, CANTAB-paired associates learning; GEE, generalised estimation equation; MZ, monozygotic; RFU, relative fluorescence unit.

Mentions: No protein passed multiple testing corrections for association with CANTAB-PAL total errors in 1999 or 2009; however, MAPKAPK5 was found to be associated with the 10-year change in CANTAB-PAL total errors (Figure 1a; β=0.48, Q=0.0059; Supplementary Tables 5–7).


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 relationship between plasma MAPKAPK5 levels and 10-year change in CANTAB-PAL in TwinsUK. Scatterplot comparing (a) plasma MAPKAPK5 levels and 10-year change in CANTAB-PAL in TwinsUK, or (b) MZ twin differences in both. Points are coloured by APOE E4 data. (a) GEEs covarying for age and taking into account twin relatedness show an association between plasma MAPKAPK5 and the 10-year change in CANTAB-PAL (β=0.48, Q=0.0059). (b) Linear regression covarying for age shows an association between plasma MAPKAPK5 and the 10-year change in CANTAB-PAL in the MZ twin difference context (β=0.55, P=0.030). CANTAB-PAL, CANTAB-paired associates learning; GEE, generalised estimation equation; MZ, monozygotic; RFU, relative fluorescence unit.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: The relationship between plasma MAPKAPK5 levels and 10-year change in CANTAB-PAL in TwinsUK. Scatterplot comparing (a) plasma MAPKAPK5 levels and 10-year change in CANTAB-PAL in TwinsUK, or (b) MZ twin differences in both. Points are coloured by APOE E4 data. (a) GEEs covarying for age and taking into account twin relatedness show an association between plasma MAPKAPK5 and the 10-year change in CANTAB-PAL (β=0.48, Q=0.0059). (b) Linear regression covarying for age shows an association between plasma MAPKAPK5 and the 10-year change in CANTAB-PAL in the MZ twin difference context (β=0.55, P=0.030). CANTAB-PAL, CANTAB-paired associates learning; GEE, generalised estimation equation; MZ, monozygotic; RFU, relative fluorescence unit.
Mentions: No protein passed multiple testing corrections for association with CANTAB-PAL total errors in 1999 or 2009; however, MAPKAPK5 was found to be associated with the 10-year change in CANTAB-PAL total errors (Figure 1a; β=0.48, Q=0.0059; Supplementary Tables 5–7).

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