Causal Evidence for Autoimmunity in Dementia?

The study covered in this summary was published on MedRxiv.org as a preprint and has not yet been peer reviewed.

Key Takeaways

• Several biomarkers may contribute to the development of dementia-associated diseases such as Alzheimer’s disease.

• Autoimmunity may be a modifiable component in diseases associated with dementia.

Why This Matters

• This study is the first large-scale, immune system- and blood–brain barrier-wide Mendelian randomization (MR) analysis to determine biomarkers for dementia.

• Novel biomarkers identified may assist in recognizing associated risk factors and aid in the development of new therapies.

• Inflammatory components associated with identified biomarkers may be modifiable with anti-inflammatory medications.

Study Design

• Databases (KEGG, ClueGO, and ConsensusPathDB) were searched for single nucleotide polymorphisms (SNPs) for biomarkers and outcomes.

  • MR was performed for over 43,643 immune system and blood–brain barrier-related (BBB) biomarkers.

  • Immune system and BBB search terms were defined using identifiers of cell types, receptors, proteins, metabolites, and genes.

  • Several publications and Uniprot were searched with the identifiers and the terms “immune” and “blood brain barrier.”  

• Researchers analyzed biomarkers of immune system and BBB and used MR to identify potential causal associations with five outcomes (Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, vascular dementia, and poor cognitive performance.

• An MR-based PRS was created using SNPs associated with identified biomarkers.

Key Results

• A total of 126 unique biomarkers were associated with neurodegenerative diseases in MR analyses (P < .000502).

  • Researchers identified 118 novel outcome-specific biomarkers that were distinct from high-risk genes associated with Alzheimer’s disease; they were characterized by inflammatory, chemokine, complement processes, antigen presenting and immune checkpoints, and BBB tight junction biomarkers.

  • Of the biomarkers, 8 were specifically associated with Alzheimer’s disease, vascular dementia, and poor cognitive performance.

• An MR-based polygenetic risk score (PRS) using 126 biomarkers for dementias was strongly associated with increased risk of all dementia-causing diseases (except Parkinson’s disease) and autoimmune disorders.

  • The PRS was also found to be associated with increased risk of thyroiditis, coronary heart disease, hyperlipidemia, and the likelihood of Crohn’s disease treatment.

Limitations

• The search protocol within the study may have missed some pertinent biomarkers and SNPs.

• Lack of data on dementia subtypes limited plasma protein analysis.

• Data analyses were completed with European ancestry samples, and PRS risk analysis may not apply to non-European samples.

Disclosures

• Funding was provided by two grants from Business Finland and multiple commercial entities, including AbbVie Inc and AstraZeneca UK Ltd.

• The authors report receiving financial support from multiple commercial, nonprofit, and governmental agencies.

This is a summary of a preprint research study, “Immune system and blood-brain barrier-wide biomarker analyses provide causal evidence for autoimmunity in dementia,” written by Joni V. Lindbohm, MD, PhD, from the University of Helsinki, Finland and colleagues on MedRxiv.org provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on MedRxiv.org.

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