Journal Article

Heritability of Alzheimer's disease–related plasma biomarkers in the Amish population

Caywood, Laura J., Herington, Sharlene D., Cuccaro, Michael L., Griswold, Anthony J., Hochstetler, Sherri D., Vance, Jeffery M., Fuzzell, Sarada L., Ogrocki, Paula, Miskimen, Kristy, Prough, Michael B., Dorfsman, Daniel A., Zaman, Andrew F., Lerner, Alan J., Lynn, Audrey, Whitehead, Patrice, Laux, Renee A., Scott, William K., Wang, Ping, Song, Yeunjoo E., Liu, Yining, Haines, Jonathan L., Pericak‐Vance, Margaret A., Adams, Larry D., Moore, Noel, Clouse, Jason E., Gulyayev, Alex

2026

Overview

INTRODUCTION Plasma biomarkers for Alzheimer's disease (AD) hold promise for disease diagnosis and prediction, yet their genetic underpinnings remain under explored. METHODS We measured plasma amyloid beta (Aβ)40, Aβ42, Aβ42/Aβ40, total tau (t‐tau), phosphorylated tau 181 (p‐tau181), Aβ42/t‐tau, Aβ42/p‐tau181, neurofilament light chain, and glial fibrillary acidic protein in the Midwestern Amish. Pedigree‐based heritability (hped2 $h_{{\\mathrm{ped}}}^2$ ) was estimated from multigenerational pedigrees, and single nucleotide polymorphism (SNP)–based heritability (hSNP2 $h_{{\\mathrm{SNP}}}^2$ ) was derived from SNPs. RESULTS Among all Amish individuals, additive genetic effects (hped2) $( {h_{{\\mathrm{ped}}}^2} )$explained 11.1% to 36.6% of biomarker variances. hSNP2 $h_{{\\mathrm{SNP}}}^2$estimates were consistently lower, ranging from 6.7% to 28.7%. The heritability of these biomarkers in subgroups of cognitively normal individuals and apolipoprotein E ε4 non‐carriers yielded similar results. DISCUSSION Plasma biomarkers such as Aβ, t‐tau, and p‐tau181 are moderately heritable in the Amish, underscoring the impact of genetic determinants of plasma biomarkers associated with AD. Highlights Plasma biomarkers for Alzheimer's disease showed moderate heritability in the Midwestern Amish. Plasma phosphorylated tau181 had the highest heritability among all biomarkers studied. Pedigree‐based heritability estimates exceeded single nucleotide polymorphism–based estimates across markers. Heritability estimates were consistent in cognitively normal and apolipoprotein E ε4 groups.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Alzheimer's disease / Amish / amyloid beta / Biomarkers / Cognitive impairment / Datasets / Dementia / Estimates / Genotype & phenotype / glial fibrillary acidic protein / heritability / neurofilament light chain / Plasma / plasma biomarkers / Polymorphism / Population / Quality control / Sample size / tau / Twin studies / Twins