Reassessing neurodegenerative disease: immune protection pathways and antagonistic pleiotropy

Abstract

The antagonistic pleiotropy (AP) theory posits that adaptive evolutionary changes, which facilitate reproduction and individual fitness early in life, can enhance detrimental aging-related processes. Several genes associated with human brain diseases play a protective role in infection, suggesting the relevance of AP in the context of brain aging and neurodegeneration. Relatedly, genetic variants that confer immune protection against pathogens may lead to uncontrolled brain inflammation later in life. Here, we propose a conceptual framework suggesting that the pleiotropic roles of genes in infections and host-pathogen interactions should be considered when studying neurological illnesses. We reinterpret recent findings regarding the impact of neurological disease-associated genetic traits on infections and chronic inflammatory diseases. Identifying the AP pathways shared among these seemingly unrelated conditions might provide further insights into the detrimental role of the immune system in brain disease as well as the mechanisms involved in chronic infections.

Keywords: Alzheimer’s disease; Parkinson’s disease; host–pathogen interactions; infections; lysosomal storage diseases.