Inflammation and Brain Structure in Alzheimer's Disease and Other Neurodegenerative Disorders: a Mendelian...

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• Inflammation's role in neurodegenerative disorders is known from in vitro studies.
• In vivo associations between inflammation, brain structure, and the genetic underpinnings of neurodegeneration remain unclear.

Purpose of the Study:

• To investigate the causal links between inflammatory genetic variants and neurodegenerative diseases.
• To explore the association between inflammation, brain structure, and the transcriptome in Alzheimer's disease (AD).

Main Methods:

• Two-sample Mendelian randomization analyses using genetic data from European ancestry GWAS.
• Analysis of single-nucleus transcriptome data from the occipitotemporal cortex in AD patients.
• Investigated genetic variants of inflammatory cytokines and their association with AD, Parkinson's disease (PD), ALS, and DLB.

Main Results:

• Genetically predicted TREM2 and soluble TREM2 (sTREM2) showed significant causal associations with AD risk.
• TREM2 genetic variants were linked to reduced cortical thickness in the temporal lobe.
• No causal associations were found for other inflammatory cytokines with AD, PD, ALS, or DLB.
• Microglia in the occipitotemporal cortex showed increased TREM2 and inflammatory gene expression in AD.

Conclusions:

• TREM2 plays a significant role in Alzheimer's disease pathogenesis, linking inflammation, brain structure, and genetic predisposition.
• Findings provide novel insights into the molecular and cellular mechanisms of TREM2 in AD.
• Highlights the complex interplay between inflammation, genetics, and brain structure in neurodegeneration.