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Genetic Risk Factors Influence Age at Onset in Autosomal Dominant Alzheimer Disease
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Key Takeaways
- APOE genotype significantly impacts age at onset in APP duplication carriers, with ε4 linked to earlier onset and ε2 delaying it.
- Polygenic risk score (PRS) influences age at onset, but its significance in survival models is limited.
A recent study presented at the 2025 AD/PD Conference identified key modifiers of Alzheimer disease onset in amyloid precursor protein duplication carriers.
Joan Groeneveld
(Credit: LinkedIn)
A newly presented analysis of autosomal dominant Alzheimer disease (ADAD) caused by amyloid precursor protein (APP) duplication has identified genetic risk factors that may influence the age at onset of the disease. The study, which examined data from 92 APP duplication carriers, reported that the APOE genotype and a polygenic risk score (PRS) for Alzheimer disease (AD) impacts the timing of symptom onset.1
Researchers assessed genetic data from 69 previously studied individuals alongside 23 additional cases from the literature. in the study, findings revealed that the presence of the APOE ε4 allele was linked to an earlier age at onset whereas the ε2 allele appeared to delay disease onset. Linear regression models indicated that APOE genotype reduced age at onset by an average of 3.5 years (P = .012), and a one-standard-deviation increase in PRS led to a 2.1-year reduction in age at onset (P = .035).
Further statistical modeling reinforced the influence of APOE, with a hazard ratio of 1.75 (95% CI, 1.15-2.67; P = .009) for earlier onset. However, findings showed that PRS did not reach statistical significance in the survival model (HR =1.33; 95% CI, 0.97-1.83; P = .081).
Beyond APOE and PRS, the study identified potential associations between age at onset and genetic variants near the GRN and INPP5D genes. The GRN variant demonstrated a hazard ratio of 2.32 (q = .06), whereas the INPP5D variant showed a protective trend (HR, .50, q = .11). Although these findings may require further validation, they suggest additional genetic factors may contribute to disease progression.
Presented by lead author Joan Groeneveld, PhD candidate in the Department of Human Genetics and Alzheimer’s Center at Amsterdam UMC, at the 2025 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), held April 1-5 in Vienna, Austria, these results provide insight into the genetic factors influencing age at onset in APP duplication carriers and highlighted potential targets for intervention. By refining age at onset prediction models, researchers may improve early identification and management strategies for individuals at risk of AD.
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While APOE genotype showed to influence the age at onset of ADAD, additional new research presented at AD/PD 2025 suggests it also plays a key role in cognitive resilience among the oldest-old patient population. A large-scale study of "SuperAgers"—individuals aged 80 and older with memory performance comparable with middle-aged adults—has identified genetic differences that may contribute to their exceptional cognitive abilities.2
Researchers analyzed longitudinal cognitive data from over 1600 SuperAgers, comparing their APOE genotypes to those of individuals with AD and cognitively normal controls. The results showed that SuperAgers were significantly more likely to carry the protective APOE-ε2 allele and less likely to carry the APOE-ε4 allele, which is associated with increased Alzheimer risk.
Among non-Hispanic White participants, SuperAgers had lower APOE-ε4 frequency than all control groups, including age-matched individuals 80 and older. In non-Hispanic Black SuperAgers, APOE-ε2 was more prevalent compared with controls, though this difference did not remain significant after statistical adjustments.
Presented by lead author Alaina Durant, statistical genetics analyst in the Vanderbilt's Memory and Alzheimer's Center, these findings further reinforce the role of APOE in brain health across the aging spectrum. By deepening our understanding of genetic contributors to both AD risk and successful cognitive aging, researchers may uncover new strategies to delay disease onset and promote brain health in older adults.
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