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. 2025 Jan;21(1):e14269.
doi: 10.1002/alz.14269. Epub 2024 Nov 26.

Heritability of Alzheimer's disease plasma biomarkers: A nuclear twin family design

Rebecca Z Rousset  1 , Anouk den Braber  2   3 , Inge M W Verberk  1 , Lynn Boonkamp  1 , David H Wilson  4 , Lannie Ligthart  3 , Charlotte E Teunissen  1 , Eco J C de Geus  3
Affiliations

Heritability of Alzheimer's disease plasma biomarkers: A nuclear twin family design

Rebecca Z Rousset et al. Alzheimers Dement. 2025 Jan.

Abstract

Introduction: Alzheimer's disease (AD) is a highly heritable disease (60%-80%). Amyloid beta (Aβ) 42/40, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) are plasma biomarkers for AD. Clinical biomarker research would be served by an understanding of the sources of variance in these markers.

Methods: Blood concentrations of Aβ42/40, NfL, and GFAP of twins and their families (monozygotic twins: 1574, dizygotic twins: 1266, other: 3657) were analyzed on the Simoa HD-X. Twin-family models were used to estimate proportional genetic contributions to the variance in biomarker levels.

Results: Heritability estimates were 16% for Aβ42/40, 42% for NfL, and 60% for GFAP. NfL and GFAP were significantly correlated with each other (0.37) but not with Aβ42/40.

Discussion: The heritability of Aβ42/40 (16%) is lower than the heritability of AD, suggesting strong environmental influences on this biomarker. The lack of correlation between NfL/GFAP and Aβ42/40 indicates these markers may be on different biological pathways.

Highlights: Heritability is found for glial fibrillary acidic protein (60%), neurofilament light chain (42%), and amyloid beta (Aβ) 42/40 (16%) plasma levels. Aβ42/40 plasma levels are sensitive to person-specific environmental influences.

Keywords: Alzheimer's disease; amyloid beta 42/40 ratio; glial fibrillary acidic protein; heritability; neurofilament light chain; twin study.

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Conflict of interest statement

CET has research contracts with Acumen, ADx Neurosciences, AC‐Immune, Alamar, Aribio, Axon Neurosciences, Beckman‐Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had consultancy/speaker contracts for Eli Lilly, Merck, Novo Nordisk, Olink, and Roche. D.W. is an employee of Quanterix. R.R., A.dB., I.V., L.B., L.L., and E.dG. have nothing to disclose. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Univariate CTD design. Single‐headed arrows indicate contributions of a latent factor on a trait. Double‐headed arrows indicate a covariance between two latent factors. A, additive genetic effect; C, shared environment effects; CTD, classical twin design; DZ, dizygotic twins; E, unique environment effects; MZ, monozygotic twins; rA = correlation between A factors of Twin 1 and Twin 2; rC = correlation between C factors of Twin 1 and Twin 2.
FIGURE 2
FIGURE 2
Bivariate model between plasma NfL and plasma GFAP. Twin 1 and Twin 2 are denoted as “1” and “.” Single‐headed arrows indicate contributions of a latent factor on a trait. Double‐headed arrows indicate a covariance between two latent factors. A, additive genetic effect; C, shared environment effects; E, unique environment effects; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain.
FIGURE 3
FIGURE 3
Simplified NTFD with siblings. To reduce complexity, the second sibling was not depicted. A, additive genetic effects; E, unique environment; F, family environment; m, familial transmission; NTFD, nuclear twin family design; S, sibling environment; T, twin‐specific environment; w, A–F covariance; μ, assortative mating.
FIGURE 4
FIGURE 4
Correlations of plasma biomarkers between different family members. Ab, amyloid beta; CI, confidence interval; DZ, dizygotic twins; GFAP, glial fibrillary acidic protein; MZ, monozygotic twins; NfL, neurofilament light chain.
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