Dataset Information

Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging.

ABSTRACT:

Background

Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults.

Objective

To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome.

Methods

Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up).

Results

Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities.

Conclusions

Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

SUBMITTER: Short MI

PROVIDER: S-EPMC10741337 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging.

Short Meghan I MI Fohner Alison E AE Skjellegrind Håvard K HK Beiser Alexa A Gonzales Mitzi M MM Satizabal Claudia L CL Austin Thomas R TR Longstreth W T WT Bis Joshua C JC Lopez Oscar O Hveem Kristian K Selbæk Geir G Larson Martin G MG Yang Qiong Q Aparicio Hugo J HJ McGrath Emer R ER Gerszten Robert E RE DeCarli Charles S CS Psaty Bruce M BM Vasan Ramachandran S RS Zare Habil H Seshadri Sudha S

Journal of Alzheimer's disease : JAD 20230101 4

<h4>Background</h4>Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults.<h4>Objective</h4>To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plas ...[more]

PMID: 38007645

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Project description:BackgroundThe need for new therapeutics for attention deficit hyperactivity disorder (ADHD) is evident. Brain, cerebrospinal fluid (CSF), and plasma protein biomarkers with causal genetic evidence could represent potential drug targets. However, a comprehensive screen of the proteome has not yet been conducted.MethodsWe employed a three-pronged approach using Mendelian Randomization (MR) and Bayesian colocalization analysis. Firstly, we studied 608 brains, 214 CSF, and 612 plasma proteins as potential causal mediators of ADHD using MR analysis. Secondly, we analysed the consistency of the discovered biomarkers across three distinct subtypes of ADHD: childhood, persistent, and late-diagnosed ADHD. Finally, we extended our analysis to examine the correlation between identified biomarkers and Tourette syndrome and pervasive autism spectrum disorder (ASD), conditions often linked with ADHD. To validate the MR findings, we conducted sensitivity analysis. Additionally, we performed cell type analysis on the human brain to identify risk genes that are notably enriched in various brain cell types.FindingsAfter applying Bonferroni correction, we found that the risk of ADHD was increased by brain proteins GMPPB, NAA80, HYI, CISD2, and HYI, TIE1 in CSF and plasma. Proteins GMPPB, NAA80, ICA1L, CISD2, TIE1, and RMDN1 showed overlapped loci with ADHD risk through Bayesian colocalization. Overexpression of GMPPB protein was linked to an increase in the risk for all three ADHD subtypes. While ICA1L provided protection against both ASD and ADHD, CISD2 increased the probability of both disorders. Cell-specific studies revealed that GMPPB, NAA80, ICA1L, and CISD2 were predominantly present on the surface of excitatory-inhibitory neurons.InterpretationOur comprehensive MR investigation of the brain, CSF, and plasma proteomes revealed seven proteins with causal connections to ADHD. Particularly, GMPPB and TIE1 emerged as intriguing targets for potential ADHD therapy.FundingThis work was partly funded by the Key R & D Program of Zhejiang (T.L. 2022C03096); the National Natural Science Foundation of China Project (C.Z. 82001413); Postdoctoral Foundation of West China Hospital (C.Z. 2020HXBH163).

Dataset Information

Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging.

Background

Objective

Methods

Results

Conclusions

Publications

Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging.

Similar Datasets

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