Genetic Architecture of Plasma Amyloid and Tau Biomarkers in the Amish
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Background
Plasma biomarkers offer a minimally invasive alternative for detecting Alzheimer’s disease (AD) pathology, yet the genetic determinants influencing their levels remain largely underexplored.
Objective
To identify genetic variants associated with AD-related plasma biomarker levels in a Midwestern Amish cohort.
Methods
We analyzed plasma levels of amyloid beta (Aβ42/Aβ40), phosphorylated tau 181 (p-tau181), and the p-tau181/Aβ42 ratio in the Midwestern Amish. Genome-wide association studies (GWAS) were used to examine associations with common genetic variants, while genetic linkage analysis was used to assess the potential impact of rare variants.
Results
GWAS found associations between plasma biomarkers and the APOE gene. Additionally, novel candidate genes were implicated, including MME for Aβ42/Aβ40 ratio, and VEGFC and LRRTM4 for p-tau181. Linkage analysis identified significant signals for p-tau181 on chromosome 1, potentially involving the CSF1 and AHCYL1 genes.
Conclusions
The novel genetic variants associated with AD pathology implicate metabolic, synaptic, neuronal, and immune pathways. The use of GWAS and linkage analysis sheds light on the genetic architecture of AD-related plasma biomarkers.
