Genotype-phenotype interaction in Alzheimer's disease immune activation.

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder with significant genetic influences, particularly concerning immune system activation.
• Understanding the interplay between genetic factors and immune responses is crucial for elucidating AD pathogenesis.

Purpose of the Study:

• To investigate genotype-phenotype interactions influencing immune responses in Alzheimer's disease.
• To examine the relationship between genetic risk scores for AD and autoimmunity and specific immune markers in cerebrospinal fluid (CSF).

Main Methods:

• Polygenic risk scores (PRSs) were computed, including AD-specific (AD PRS_INFL), immune-related (sum PRS_IMMUNE), and standard AD PRSs for 294 individuals.
• Cerebrospinal fluid (CSF) immune markers (sTREM2, clusterin, fractalkine, YKL-40) were analyzed in relation to PRSs and neurodegeneration markers (total tau [t-tau], neurofilament light chain [NfL]).

Main Results:

• Higher AD PRS_INFL was associated with lower sTREM2, clusterin, and fractalkine levels in individuals with elevated t-tau.
• A higher sum PRS_IMMUNE correlated with lower clusterin levels in individuals with elevated NfL.

Conclusions:

• Genetic predisposition towards immune activation may contribute to adverse immune responses in the early stages of Alzheimer's disease.
• Polygenic risk scores effectively capture genotype-phenotype associations related to immune activation in AD, highlighting the importance of specific genetic factors in early AD immune phenotypes.