Heritability of Alzheimer-related plasma biomarkers in the Amish population

Abstract

Introduction: Plasma biomarkers for Alzheimer disease (AD) hold promise for disease diagnosis and prediction, yet their genetic underpinnings remain underexplored.

Methods: We measured plasma amyloid beta 40 (Aβ40), 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 $\left(h_{\text{ped}}^2\right)$ was estimated from multigenerational pedigrees, and SNP-based heritability ${(h}_{SNP}^2)$ was derived from single nucleotide polymorphisms (SNPs).

Results: Among all Amish individuals, additive genetic effects $\left(h_{\text{ped}}^2\right)$ explained 11.1% to 36.6% of biomarker variances. $h_{SNP}^2$ estimates were consistently lower, ranging from 6.7% to 28.7%. The heritability of these biomarkers in subgroups of cognitively normal individuals and APOE ε4 non-carriers yielded similar results.

Discussion: Plasma biomarkers such as amyloid β, t-tau, and p-tau181 are moderately heritable in the Amish, underscoring the impact of genetic determinants of plasma biomarkers associated with AD.

Keywords: Amish; Amyloid Beta; GFAP; Heritability; NfL; Plasma Biomarkers; Tau.