Interaction of Genetics, Amyloid-beta and Inflammation as Mediators of Brain Structure Change in Cognitive Decline

Abstract

Abstract In the presence of AD pathologies, the genetic architecture of brain structure changes related to progressive cognitive deterioration is not well examined. Here, we seek to shed light in the interplay of inflammation, amyloid-beta, and genetic background influencing brain structure changes. We studied 12-month changes in neuroimaging, inflammation and Aβ42/Aβ40 in 1322 individuals (ADNI cohort) and ran GWAS as well as SNP effect concordance analysis to test for genetic pleiotropy of identified risk variants. We uncovered genome-wide significant hits for structural change in nine brain regions, as well as change in inflammatory and Aβ42/Aβ40 biomarkers. We also found significant evidence of pleiotropy and concordance for several of the implicated genetic variants. Conditioning on inflammatory and Aβ42/Aβ40 biomarkers, novel variants that underlie brain structure change were identified. Amyloid-beta could interact with inflammatory biomarkers to affect brain structures via SNP-SNP interaction. Our findings point to the Interaction of amyloid-beta and inflammation as mediators of brain structure change and associated cognitive decline in AD and shed light into the underlying genetic background.