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

Rebecca Z. Rousset; Anouk den Braber; Inge M. W. Verberk; Lynn Boonkamp; David H. Wilson; Lannie Ligthart; Charlotte E. Teunissen; Eco J. C. de Geus

doi:10.1002/alz.14269

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

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

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	e14269
Pages (from-to)	1-13
Number of pages	13
Journal	Alzheimer's & Dementia
Volume	21
Issue number	1
Early online date	26 Nov 2024
DOIs	https://doi.org/10.1002/alz.14269
Publication status	Published - Jan 2025

Funding

We thank the twins and family members of the Netherland Twin Register for their participation in this study. The study was approved by the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Centre, Amsterdam, an institutional review board certified by the U.S. Office of Human Research Protections (IRB number IRB00002991 under Federal‐wide Assurance‐ FWA00017598; IRB/institute codes, NTR 03‐180). Funding for blood sample collection was obtained from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW) grants 904‐61‐090, 985‐10‐002, 904‐61‐193, 480‐04‐004, 400‐05‐717, Addiction‐31160008, 016‐115‐035, 400‐07‐080, Middelgroot‐911‐09‐032, NWO‐Groot 480‐15‐001/674; the European Community's Fifth and Seventh Framework Program (FP5‐ LIFE QUALITY‐CT‐2002‐2006, FP7‐ HEALTH‐F4‐2007‐2013, grant 01254: GenomEUtwin, grant 01413: ENGAGE). Funding for the bioassays and research by RR costs came from the CANTATE project. The CANTATE project is funded by the Alzheimer Drug Discovery Foundation. Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking [JU], grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CT is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMw (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). CT is recipient of TAP‐dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. We thank the twins and family members of the Netherland Twin Register for their participation in this study. The study was approved by the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Centre, Amsterdam, an institutional review board certified by the U.S. Office of Human Research Protections (IRB number IRB00002991 under Federal-wide Assurance- FWA00017598; IRB/institute codes, NTR 03-180). Funding for blood sample collection was obtained from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW) grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 016-115-035, 400-07-080, Middelgroot-911-09-032, NWO-Groot 480-15-001/674; the European Community's Fifth and Seventh Framework Program (FP5- LIFE QUALITY-CT-2002-2006, FP7- HEALTH-F4-2007-2013, grant 01254: GenomEUtwin, grant 01413: ENGAGE). Funding for the bioassays and research by RR costs came from the CANTATE project. The CANTATE project is funded by the Alzheimer Drug Discovery Foundation. Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking [JU], grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CT is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMw (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). CT is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy.

Funders	Funder number
Alzheimer's Association
Dutch National Dementia Strategy
Health Holland
EPND
Seventh Framework Programme
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
National Multiple Sclerosis Society
EU Joint Programme – Neurodegenerative Disease Research
NWO-Groot
HEALTH-F4-2007-2013
Alzheimer's Drug Discovery Foundation
ZonMw	480‐15‐001/674, 904‐61‐090, 400‐05‐717, 016‐115‐035, Middelgroot‐911‐09‐032, 985‐10‐002, 10510032120003, 73305095007, 400‐07‐080, 480‐04‐004, 904‐61‐193
VU University Medical Centre	IRB00002991, FWA00017598, NTR 03-180
European Community's Fifth and Seventh Framework Program	FP5‐ LIFE QUALITY‐CT‐2002‐2006, 01254, 01413
Innovative Medicines Initiative	101034344
European Commission	860197, 831434

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@article{99f05ec26a5c4556bdf8ebf59fd2fc54,

title = "Heritability of Alzheimer's disease plasma biomarkers: A nuclear twin family design",

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. ",

author = "Rousset, \{Rebecca Z.\} and \{den Braber\}, Anouk and Verberk, \{Inge M. W.\} and Lynn Boonkamp and Wilson, \{David H.\} and Lannie Ligthart and Teunissen, \{Charlotte E.\} and \{de Geus\}, \{Eco J. C.\}",

year = "2025",

month = jan,

doi = "10.1002/alz.14269",

language = "English",

volume = "21",

pages = "1--13",

journal = "Alzheimer's \& Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc.",

number = "1",

}

TY - JOUR

T1 - Heritability of Alzheimer's disease plasma biomarkers: A nuclear twin family design

AU - Rousset, Rebecca Z.

AU - den Braber, Anouk

AU - Verberk, Inge M. W.

AU - Boonkamp, Lynn

AU - Wilson, David H.

AU - Ligthart, Lannie

AU - Teunissen, Charlotte E.

AU - de Geus, Eco J. C.

PY - 2025/1

Y1 - 2025/1

N2 - 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.

AB - 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.

U2 - 10.1002/alz.14269

DO - 10.1002/alz.14269

M3 - Article

SN - 1552-5260

VL - 21

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JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

IS - 1

M1 - e14269

ER -

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

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Funding

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