Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component...

Area of Science:

• Neuroimmunology
• Genetics
• Pharmacology

Background:

• Immune system and blood-brain barrier dysfunction are linked to Alzheimer's disease and other dementias.
• The precise causal role of these factors in dementia development is not fully understood.

Purpose of the Study:

• To investigate the causal relationship between immune system and blood-brain barrier biomarkers and dementia.
• To explore potential therapeutic targets for dementia prevention and treatment.

Main Methods:

• Mendelian randomization was used to analyze 1,827 immune and blood-brain barrier biomarkers for causal links to dementia.
• Pathway and phenome-wide analyses, including polygenic risk scores in the FinnGen study, were conducted.
• Inverse-probability-weighted analyses examined the effect of anti-inflammatory treatment on dementia incidence.

Main Results:

• 127 potential causal risk factors for dementia were identified.
• Biomarkers were linked to amyloid-β, tau, α-synuclein, and autoimmunity pathways.
• A shared genetic background between dementias and autoimmune diseases was indicated.
• Methotrexate treatment significantly reduced Alzheimer's disease incidence in high-risk individuals.

Conclusions:

• Autoimmunity is suggested as a modifiable component in dementia development.
• These findings support targeting autoimmune pathways for dementia prevention and treatment.