Genetic Architecture of Plasma Amyloid and Tau Biomarkers in the Amish

Ping Wang; Dana Z. Jian; Yeunjoo E. Song; Audrey Lynn; Kristy L. S. Miskimen; Patrice G. Whitehead; Alex V. Gulyayev; Michael B. Prough; Daniel A. Dorfsman; Reneé A. Laux; Sarada L. Fuzzell; Dawn Miller; Sherri D. Hochstetler; Penelope L. Miron; Andrew F. Zaman; Larry Deon Adams; Laura J. Caywood; Jason E. Clouse; Sharlene D. Herington; Yining Liu; Noel C. Moore; Paula K. Ogrocki; Alan Jay Lerner; Anthony J. Griswold; Michael L. Cuccaro; Jeffery M. Vance; William K. Scott; Margaret A. Pericak‐Vance; Jonathan L. Haines

doi:10.64898/2026.10.15.26365636

Genetic & Genomic MedicinemedRxivOct 19, 2026

Preprint

Genetic Architecture of Plasma Amyloid and Tau Biomarkers in the Amish

Ping Wang iD, Dana Z. Jian iD, Yeunjoo E. Song iD, Audrey Lynn, Kristy L. S. Miskimen iD, Patrice G. Whitehead, Alex V. Gulyayev, Michael B. Prough, Daniel A. Dorfsman, Reneé A. Laux, Sarada L. Fuzzell, Dawn Miller, Sherri D. Hochstetler, Penelope L. Miron iD, Andrew F. Zaman iD, Larry Deon Adams, Laura J. Caywood, Jason E. Clouse, Sharlene D. Herington, Yining Liu, Noel C. Moore, Paula K. Ogrocki, Alan Jay Lerner iD, Anthony J. Griswold iD, Michael L. Cuccaro iD, , Jonathan L. Haines iD

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Abstract

BackgroundPlasma biomarkers offer a minimally invasive alternative for detecting Alzheimers disease (AD) pathology, yet the genetic determinants influencing their levels remain largely underexplored. ObjectiveTo identify genetic variants associated with AD-related plasma biomarker levels in a Midwestern Amish cohort. MethodsWe analyzed plasma levels of amyloid beta (A{beta}42/A{beta}40), phosphorylated tau 181 (p-tau181), and the p-tau181/A{beta}42 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. ResultsGWAS found associations between plasma biomarkers and the APOE gene. Additionally, novel candidate genes were implicated, including MME for A{beta}42/A{beta}40 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. ConclusionsThe 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.