Genotype–phenotype interaction in Alzheimer's disease immune activation

Abstract INTRODUCTION Alzheimer's disease (AD) is a neurodegenerative disorder influenced by genetic factors, particularly related to immune activation. This study examines genotype‐phenotype interactions affecting immune responses in AD as a reaction to neurodegeneration. METHODS We computed AD polygenic risk scores (PRSs) informed by shared AD‐autoimmunity genetics (AD PRS INFL ), AD‐independent immune activation score from 10 autoimmune diseases (sum PRS IMMUNE ), and standard AD PRSs for 294 individuals. Cerebrospinal fluid (CSF) immune markers (sTREM2, clusterin, fractalkine, and chitinase 3 like protein (YKL‐40)) were regressed on PRSs, and their interaction with neurodegeneration markers (total tau [t‐tau] or neurofilament light chain [NfL]). RESULTS High AD PRS INFL scores correlated with lower sTREM2 ( β = −0.18, p < 0.01), clusterin ( β = −0.12, p < 0.05), and fractalkine ( β = −0.13, p < 0.05) levels in cases with elevated t‐tau. High sum PRS IMMUNE score correlated with lower clusterin in cases with elevated NfL ( β = −0.12, p < 0.05). DISCUSSION Genetic predisposition for immune activation might cause unfavorable immune response in early AD. Highlights High genetic risk relates to cerebrospinal fluid (CSF) immune markers amid evident neurodegeneration Immune polygenic risk scores (PRSs) capture genotype‐phenotype associations in Alzheimer's disease (AD) immune activation AD PRSs and immune phenotype had an opposite relationship of the phenotype PRSs Importance of specific genetic predispositions in early AD immune phenotypes