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Alzheimer's Association International Conference 2026

July 12-15, 2026 | London, United Kingdom, and Online

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2649

Genetic Risk Factors, Including APOE, Modify Onset Of Alzheimer’s Disease In Carriers Of An Extra Copy Of APP, With And Without Down Syndrome

Poster Presenter

Joan Groeneveld

Authors

Joan Groeneveld, Danna Perlaza, Clàudia Olivé, Lou Grangeon, Niccolo Tesi, Aude Nicolas, Chenyang Jiang, Itziar de Rojas, David Wallon, Stéphane Rousseau, Marta Rovira, Diego Real de Asúa, Fernando Moldenhauer, Ruihao Mu, Kévin Cassinari, Aline Zarea, Joaquim Aumatell Escabias, Jean-Charles Lambert, Yolande Pijnenburg, Marc Hulsman, Everard Vijverberg, Johannes Levin, Mathias Jucker, Eric McDade, Juan Fortea, Henne Holstege, Flora Duits, Lisa Vermunt, Maulikkumar Patel, Matthew Johnson, Alan Renton, Alison Goate, Carlos Cruchaga, Cyril Pottier, Maria Fernandez, Olivia Belbin, Gael Nicolas, Oriol Dols-Icardo, Sven van der Lee, Dominantly Inherited Alzheimer Network -

Affiliations

, Amsterdam UMC

Part of Topic

BACKGROUND:
● APP duplications (APPdup) & Down syndrome (DS) cause excess amyloid-β production and early-onset Alzheimer’s disease (AD).1
● Age at onset (AAO) varies considerably among these carriers of an extra APP copy.2-5
● The contribution of APOE and other AD risk variants to this variability is not yet established.5-7

AIM: To investigate the impact of APOE genotype and AD genetic risk scores on age at onset in carries of an extra copy of APP

METHODS:
Population:
● APP duplication carriers (n=100)
● Down syndrome individuals (n=957)

Genetics: SNP array / whole-genome sequencing
● APOE genotype
● AD genetic risk score (AD-GRS; 77 SNPs)
● Pathway-specific AD-GRS (beta-amyloid, angiogenesis, endocytosis, immune response, cholesterol/lipid)
 
Analysis:
● Kaplan-Meier curves
● Cox regression analyses for AAO
● Cumulative incidence curves
 
RESULTS:
● AAO was earlier in APPdup than in DS (50.7 vs 53.3 years), but variability in AAO was comparable between groups.
● APOE ε2 delayed, whereas APOE ε4 accelerated onset.
● A higher AD-GRS was associated with earlier onset.
● APOE and AD-GRS effects combined showed a ~10-year difference in AAO between the lowest and highest risk.
● Pathway analyses implicated β-amyloid and angiogenesis pathways as modifiers of AAO.
 
CONCLUSION:
● AD genetic risk factors modify age at onset in individuals with an extra APP copy, resulting in a ~10-year difference between low and high genetic risk.
● This may improve prognosis & optimize timing of future disease-modifying therapies.

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