# Genotype–phenotype interaction in Alzheimer's disease immune activation

## TL;DR

This study explores how genetic risk factors for Alzheimer's disease influence immune responses in the brain, especially when neurodegeneration is present.

## Contribution

The study introduces immune-related polygenic risk scores to analyze genotype-phenotype interactions in Alzheimer's immune activation.

## Key findings

- High AD PRSINFL scores correlate with lower levels of sTREM2, clusterin, and fractalkine in individuals with elevated t-tau.
- High sum PRSIMMUNE scores correlate with lower clusterin in individuals with elevated NfL.
- Genetic predisposition for immune activation may lead to unfavorable immune responses in early Alzheimer's disease.

## Abstract

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.

We computed AD polygenic risk scores (PRSs) informed by shared AD‐autoimmunity genetics (AD PRSINFL), AD‐independent immune activation score from 10 autoimmune diseases (sum PRSIMMUNE), 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]).

High AD PRSINFL 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 PRSIMMUNE score correlated with lower clusterin in cases with elevated NfL (β = −0.12, p < 0.05).

Genetic predisposition for immune activation might cause unfavorable immune response in early AD.

High genetic risk relates to cerebrospinal fluid (CSF) immune markers amid evident neurodegenerationImmune polygenic risk scores (PRSs) capture genotype‐phenotype associations in Alzheimer's disease (AD) immune activationAD PRSs and immune phenotype had an opposite relationship of the phenotype PRSsImportance of specific genetic predispositions in early AD immune phenotypes

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