Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium

Emma S Luckett; Yasmina Abakkouy; Luigi Lorenzini; Lyduine E Collij; David Vallez Garcia; Pieter Jelle Visser; Anouk den Braber; Craig Ritchie; Mercè Boada; Patricia Genius; Natàlia Vilor-Tejedor; Juan Domingo Gispert; Rik Vandenberghe; Frederik Barkhof; Isabelle Cleynen; AMYPAD Consortium

doi:10.1002/alz.70376

Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium

Emma S Luckett^*, Yasmina Abakkouy, Luigi Lorenzini, Lyduine E Collij, David Vallez Garcia, Pieter Jelle Visser, Anouk den Braber, Craig Ritchie, Mercè Boada, Patricia Genius, Natàlia Vilor-Tejedor, Juan Domingo Gispert, Rik Vandenberghe, Frederik Barkhof, Isabelle Cleynen, AMYPAD Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

INTRODUCTION: We sought to harmonize genotype data from the predementia AMYPAD (Amyloid Imaging to Prevent Alzheimer's Disease) Consortium, compute polygenic risk scores (PRS), and determine their association with global amyloid deposition.
METHODS: Genetic data from five AMYPAD parent cohorts were harmonized, and PRS were computed for Alzheimer's disease (AD) susceptibility, cerebrospinal fluid (CSF) amyloid beta (Aβ)42, and CSF phosphorylated tau181. Cross-sectional amyloid (Centiloid [CL]) burden was available for all participants, and regression models determined if PRS were associated with CL burden.
RESULTS: After harmonization, data for 867 participants showed that high CL burden was most strongly predicted by CSF Aβ42 PRS compared to traditional AD susceptibility PRS.
DISCUSSION: This work emphasizes the importance of data harmonization and pooling of cohorts for large-powered studies. Findings suggest a genetic predisposition to amyloid pathology that may predispose individuals early in the AD continuum. This validates the potential use of PRS in clinical (trial) settings as a non-invasive tool to assess AD risk.

Original language	English
Article number	e70376
Pages (from-to)	1-14
Number of pages	14
Journal	Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume	21
Issue number	9
DOIs	https://doi.org/10.1002/alz.70376
Publication status	Published - Sept 2025

Keywords

Aged
Male
Brain - metabolism - pathology - diagnostic imaging
tau Proteins - cerebrospinal fluid
Genotype
Amyloid
Alzheimer's disease
Polygenic risk scores
Peptide fragments - cerebrospinal fluid
Amyloid imaging to prevent Alzheimer's disease
Female
Genetic predisposition to disease - genetics
Predementia
Cohort studies
Humans
Alzheimer disease - genetics - diagnostic imaging
Middle aged
Amyloid beta-peptides - cerebrospinal fluid
Genotype data harmonization
Cross-sectional studies

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10.1002/alz.70376Licence: CC BY-NC-ND

Luckett-2025-Harmonizing-genotype-array-Alzheimers&Dementia-e70376-CCBYNCND
Copyright © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Final published version, 2.69 MBLicence: CC BY-NC-ND

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Luckett, E. S., Abakkouy, Y., Lorenzini, L., Collij, L. E., Garcia, D. V., Visser, P. J., den Braber, A., Ritchie, C., Boada, M., Genius, P., Vilor-Tejedor, N., Gispert, J. D., Vandenberghe, R., Barkhof, F., Cleynen, I., & AMYPAD Consortium (2025). Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 21(9), 1-14. Article e70376. https://doi.org/10.1002/alz.70376

@article{eda5f9041a7b4d8dbde695b34951d4b5,

title = "Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium",

abstract = "INTRODUCTION: We sought to harmonize genotype data from the predementia AMYPAD (Amyloid Imaging to Prevent Alzheimer's Disease) Consortium, compute polygenic risk scores (PRS), and determine their association with global amyloid deposition. METHODS: Genetic data from five AMYPAD parent cohorts were harmonized, and PRS were computed for Alzheimer's disease (AD) susceptibility, cerebrospinal fluid (CSF) amyloid beta (Aβ)42, and CSF phosphorylated tau181. Cross-sectional amyloid (Centiloid [CL]) burden was available for all participants, and regression models determined if PRS were associated with CL burden. RESULTS: After harmonization, data for 867 participants showed that high CL burden was most strongly predicted by CSF Aβ42 PRS compared to traditional AD susceptibility PRS. DISCUSSION: This work emphasizes the importance of data harmonization and pooling of cohorts for large-powered studies. Findings suggest a genetic predisposition to amyloid pathology that may predispose individuals early in the AD continuum. This validates the potential use of PRS in clinical (trial) settings as a non-invasive tool to assess AD risk.",

keywords = "Aged, Male, Brain - metabolism - pathology - diagnostic imaging, tau Proteins - cerebrospinal fluid, Genotype, Amyloid, Alzheimer's disease, Polygenic risk scores, Peptide fragments - cerebrospinal fluid, Amyloid imaging to prevent Alzheimer's disease, Female, Genetic predisposition to disease - genetics, Predementia, Cohort studies, Humans, Alzheimer disease - genetics - diagnostic imaging, Middle aged, Amyloid beta-peptides - cerebrospinal fluid, Genotype data harmonization, Cross-sectional studies",

author = "Luckett, {Emma S} and Yasmina Abakkouy and Luigi Lorenzini and Collij, {Lyduine E} and Garcia, {David Vallez} and Visser, {Pieter Jelle} and {den Braber}, Anouk and Craig Ritchie and Merc{\`e} Boada and Patricia Genius and Nat{\`a}lia Vilor-Tejedor and Gispert, {Juan Domingo} and Rik Vandenberghe and Frederik Barkhof and Isabelle Cleynen and {AMYPAD Consortium}",

note = "Funding: Innovative Medicines Initiative, Grant/Award Number: No 115952; European Union{\textquoteright}s Horizon 2020 research; innovation programme; GE Healthcare; Springer Healthcare; MSCA, Grant/Award Number: #101108819; Alzheimer Association Research Fellowship, Grant/Award Number: #23AARF-1029663; Spanish Research Agency, Grant/Award Numbers: MICIU/AEI/10.13039/501100011033, RYC2022-038136-I; European Union FSE+, Grant/Award Number: PID2022-143106OA-I00; European Union FEDER; Alzheimer{\textquoteright}s Disease Data Initiative; 23S06083-001; Stichting Alzheimer Onderzoek; Internal Funds KU Leuven; Flemish Research Foundation, Grant/Award Numbers: G0G1519N, G094418N; VLAIO, Grant/Award Number: HBC.2019.2523; NIHR biomedical research centre.",

year = "2025",

month = sep,

doi = "10.1002/alz.70376",

language = "English",

volume = "21",

pages = "1--14",

journal = "Alzheimer's & Dementia: The Journal of the Alzheimer's Association",

issn = "1552-5260",

publisher = "John Wiley & Sons, Ltd",

number = "9",

}

Luckett, ES, Abakkouy, Y, Lorenzini, L, Collij, LE, Garcia, DV, Visser, PJ, den Braber, A, Ritchie, C, Boada, M, Genius, P, Vilor-Tejedor, N, Gispert, JD, Vandenberghe, R, Barkhof, F, Cleynen, I & AMYPAD Consortium 2025, 'Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium', Alzheimer's & Dementia: The Journal of the Alzheimer's Association, vol. 21, no. 9, e70376, pp. 1-14. https://doi.org/10.1002/alz.70376

TY - JOUR

T1 - Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium

AU - Luckett, Emma S

AU - Abakkouy, Yasmina

AU - Lorenzini, Luigi

AU - Collij, Lyduine E

AU - Garcia, David Vallez

AU - Visser, Pieter Jelle

AU - den Braber, Anouk

AU - Ritchie, Craig

AU - Boada, Mercè

AU - Genius, Patricia

AU - Vilor-Tejedor, Natàlia

AU - Gispert, Juan Domingo

AU - Vandenberghe, Rik

AU - Barkhof, Frederik

AU - Cleynen, Isabelle

AU - AMYPAD Consortium

N1 - Funding: Innovative Medicines Initiative, Grant/Award Number: No 115952; European Union’s Horizon 2020 research; innovation programme; GE Healthcare; Springer Healthcare; MSCA, Grant/Award Number: #101108819; Alzheimer Association Research Fellowship, Grant/Award Number: #23AARF-1029663; Spanish Research Agency, Grant/Award Numbers: MICIU/AEI/10.13039/501100011033, RYC2022-038136-I; European Union FSE+, Grant/Award Number: PID2022-143106OA-I00; European Union FEDER; Alzheimer’s Disease Data Initiative; 23S06083-001; Stichting Alzheimer Onderzoek; Internal Funds KU Leuven; Flemish Research Foundation, Grant/Award Numbers: G0G1519N, G094418N; VLAIO, Grant/Award Number: HBC.2019.2523; NIHR biomedical research centre.

PY - 2025/9

Y1 - 2025/9

N2 - INTRODUCTION: We sought to harmonize genotype data from the predementia AMYPAD (Amyloid Imaging to Prevent Alzheimer's Disease) Consortium, compute polygenic risk scores (PRS), and determine their association with global amyloid deposition. METHODS: Genetic data from five AMYPAD parent cohorts were harmonized, and PRS were computed for Alzheimer's disease (AD) susceptibility, cerebrospinal fluid (CSF) amyloid beta (Aβ)42, and CSF phosphorylated tau181. Cross-sectional amyloid (Centiloid [CL]) burden was available for all participants, and regression models determined if PRS were associated with CL burden. RESULTS: After harmonization, data for 867 participants showed that high CL burden was most strongly predicted by CSF Aβ42 PRS compared to traditional AD susceptibility PRS. DISCUSSION: This work emphasizes the importance of data harmonization and pooling of cohorts for large-powered studies. Findings suggest a genetic predisposition to amyloid pathology that may predispose individuals early in the AD continuum. This validates the potential use of PRS in clinical (trial) settings as a non-invasive tool to assess AD risk.

AB - INTRODUCTION: We sought to harmonize genotype data from the predementia AMYPAD (Amyloid Imaging to Prevent Alzheimer's Disease) Consortium, compute polygenic risk scores (PRS), and determine their association with global amyloid deposition. METHODS: Genetic data from five AMYPAD parent cohorts were harmonized, and PRS were computed for Alzheimer's disease (AD) susceptibility, cerebrospinal fluid (CSF) amyloid beta (Aβ)42, and CSF phosphorylated tau181. Cross-sectional amyloid (Centiloid [CL]) burden was available for all participants, and regression models determined if PRS were associated with CL burden. RESULTS: After harmonization, data for 867 participants showed that high CL burden was most strongly predicted by CSF Aβ42 PRS compared to traditional AD susceptibility PRS. DISCUSSION: This work emphasizes the importance of data harmonization and pooling of cohorts for large-powered studies. Findings suggest a genetic predisposition to amyloid pathology that may predispose individuals early in the AD continuum. This validates the potential use of PRS in clinical (trial) settings as a non-invasive tool to assess AD risk.

KW - Aged

KW - Male

KW - Brain - metabolism - pathology - diagnostic imaging

KW - tau Proteins - cerebrospinal fluid

KW - Genotype

KW - Amyloid

KW - Alzheimer's disease

KW - Polygenic risk scores

KW - Peptide fragments - cerebrospinal fluid

KW - Amyloid imaging to prevent Alzheimer's disease

KW - Female

KW - Genetic predisposition to disease - genetics

KW - Predementia

KW - Cohort studies

KW - Humans

KW - Alzheimer disease - genetics - diagnostic imaging

KW - Middle aged

KW - Amyloid beta-peptides - cerebrospinal fluid

KW - Genotype data harmonization

KW - Cross-sectional studies

U2 - 10.1002/alz.70376

DO - 10.1002/alz.70376

M3 - Article

C2 - 40947441

SN - 1552-5260

VL - 21

SP - 1

EP - 14

JO - Alzheimer's & Dementia: The Journal of the Alzheimer's Association

JF - Alzheimer's & Dementia: The Journal of the Alzheimer's Association

IS - 9

M1 - e70376

ER -

Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium

Abstract

Keywords

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