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. 2021 Sep 14;13(1):e12229.
doi: 10.1002/dad2.12229. eCollection 2021.

Risk of dementia in APOE ε4 carriers is mitigated by a polygenic risk score

Jarith L Ebenau  1 , Sven J van der Lee  1   2 , Marc Hulsman  1   2   3 , Niccolò Tesi  1   2   3 , Iris E Jansen  1   4 , Inge M W Verberk  1   5 , Mardou van Leeuwenstijn  1 , Charlotte E Teunissen  5 , Frederik Barkhof  6   7 , Niels D Prins  1 , Philip Scheltens  1 , Henne Holstege  1   2   3 , Bart N M van Berckel  1   6 , Wiesje M van der Flier  1   8
Affiliations

Risk of dementia in APOE ε4 carriers is mitigated by a polygenic risk score

Jarith L Ebenau et al. Alzheimers Dement (Amst). .

Abstract

Introduction: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia.

Methods: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The APOE gene was not included in the PRS and was analyzed separately.

Results: The PRS and APOE ε4 were associated with amyloid-positive ATN profiles, and APOE ε4 additionally with isolated increased tau (A-T+N-). A high PRS and APOE ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers.

Discussion: Genetic variants beyond APOE are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.

Keywords: APOE; ATN classification; Alzheimer's disease; biomarkers; dementia; polygenic risk score; subjective cognitive decline.

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Conflict of interest statement

Jarith L. Ebenau, Sven J. van der Lee, Marc Hulsman, Niccolò Tesi, Iris E. Jansen, Inge M.W. Verberk, and Mardou van Leeuwenstijn report no conflicts of interest. Charlotte E. Teunissen serves on the advisory board of Roche; performed contract research or received grants from AC‐Immune, ADxNeurosciences, Boehringer, Brainstorm Therapeutics, Celgene, EIP Pharma, PeopleBio, Vivoryon, Roche, Toyama Fujifilm, Esai, and Probiodrug; and received lecture fees from Biogen and Axon Neurosciences. Her research is supported by the European Commission (Marie Curie International Training Network, and JPND), Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW and Health∼Holland, Topsector Life Sciences & Health. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes‐Strijbis fonds. CT has a collaboration contract with ADx Neurosciences and Quanterix. CT is editor at Alzheimer's Research & Therapy, Neurology: Neuroimmunology & Neuroinflammation and Medidact Neurology, and edited a volume in the series Neuromethods (Springer). Frederik Barkhof is a consultant for Biogen‐Idec, Bayer‐Schering, Merck‐Serono, Roche, NovartisIXICO, and Combinostics; has received sponsoring from European Commission‐Horizon 2020, National Institute for Health Research‐University College London Hospitals Biomedical Research Centre, TEVA, Novartis, and Biogen; and serves on the editorial boards of Radiology, Brain, Neuroradiology, Multiple Sclerosis Journal, and Neurology. Niels D. Prins is consultant to Boehringer Ingelheim, Aribio, and Amylyx. He is co‐PI of a study with Fuji Film Toyama Chemical. He serves on the DSMB of Abbvie's M15‐566 trial. NP has received a speaker fee from Biogen. Payments were made to his company. He is CEO and co‐owner of the Brain Research Center, the Netherlands. Philip Scheltens has acquired grant support (for the institution) from Biogen. In the past two years, he has received consultancy/speaker fees (paid to the institution) from Probiodrug Biogen, EIP Pharma, Merck AG. Henne Holstege received funding from Aegon, Health ∼ Holland, Hans und Ilse Breuer Stiftung, JPND research, 100‐plus enabling, and Alzheimer Nederland. All funding is paid to her institution. Bart N.M. van Berckel has received funding from ZonMW, the Netherlands Organization of Scientific Research, the Centre of Translational Molecular Imaging, and Avid Radiopharmaceuticals. All funding is paid to his institution. Wiesje M. van der Flier Research programs have been funded by ZonMW, NWO, EU‐FP7, EU‐JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes‐Strijbis fonds, stichting Equilibrio, Pasman stichting, Biogen MA Inc, Boehringer Ingelheim, Life‐MI, AVID, Roche BV, Fujifilm, Combinostics. WF holds the Pasman chair. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. WF has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, and WebMD Neurology (Medscape). WF is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. WF is associate editor at Alzheimer's Research & Therapy. All funding is paid to her institution.

Figures

FIGURE 1
FIGURE 1
Flowchart of participant selection. ADC, Amsterdam Dementia Cohort; FU, follow‐up; SCD, subjective cognitive decline; SCIENCe, subjective cognitive impairment cohort
FIGURE 2
FIGURE 2
Associations between genetic variants and biomarkers. Values given are odds ratio (95% confidence interval) corrected for age, sex, and population substructure, as estimated by logistic regression (predictor: APOE ε4 allele or normalized PRS; outcome: (A) dichotomous biomarker status for A, T, and N separately (reference = negative biomarker status), (B) eight‐profile ATN classification (reference = A–T–N–), (C) three‐category ATN classification (reference = Normal AD biomarkers). The odds ratio for the PRS reflects the odds of having an abnormal biomarker status or being classified in one of the ATN profiles with abnormal biomarkers, per one standard deviation increase in the PRS. APOE ε4 is per allele. * P‐value < .05. APOE, apolipoprotein E; ATN, amyloid/tau/neurodegeneration; OR, odds ratio; PRS, polygenic risk score
FIGURE 3
FIGURE 3
Combined effect of APOE ε4 and PRS on risk of clinical progression to AD dementia. Kaplan Meier curve showing the combined effects of APOE ε4 and the PRS on risk of progression to AD dementia, comparing (1) APOE ε4 non‐carrier and low PRS, (2) APOE ε4 non‐carrier and high PRS, (3) APOE ε4 carrier and low PRS, and (4) APOE ε4 carrier and high PRS. APOE ε4 status is determined by having one or two ε4 alleles, PRS status is based on median risk.AD, Alzheimer's disease; APOE, apolipoprotein E; PRS, polygenic risk score
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