Age Modifies the Association Between Apolipoprotein E Genotype and Alzheimer's Disease: A CSF Biomarker-Based Multicentric Case-Control Study

Background: We investigated the global and age-specific association between Apolipoprotein E (APOE) genotype and Alzheimer's disease (AD) in a large multicentric case-control study, using cerebrospinal fluid (CSF) biomarkers-based diagnostic criteria for AD. Methods: In this case-control design, data on 1,599 Caucasian AD cases with abnormal values of CSF biomarkers came from 9 European memory clinics and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. AD cases were compared to 11,724 dementia-free controls, drawn from two longitudinal cohort studies (Whitehall II and 3-City). Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were reported, overall and by 5-year age categories. Findings. 63*4% of CSF biomarker-defined AD patients and 22*6% of population controls carried at least one APOE e4 allele; respective percentages for APOE e4 homozygotes were 16*7% and 1*4%. Compared to none4 carriers, heterozygous e4 carriers had a 4*6 (95% confidence interval: 4*1 - 5*2) and e4/e4 homozygotes a 25*4 (20*5 - 31*3) higher OR of AD. This association was strongly modified by age (p for interaction < 0*001). The PAF associated with carrying at least one e4 allele was greatest in the 65-70 age group (69*7%), and weaker before 55 years (14*2%) and after 85 years (22*6%). There was some evidence of a stronger effect of APOE on AD risk in women. Interpretation: Incorporating biomarkers for diagnosis of AD led to a stronger association with APOE e4 than previously reported, perhaps due to better diagnostic accuracy. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE e4 at the population level. Funding Statement: US National Institutes of Health, Fondation Plan Alzheimer. Declaration of Interests: ASM is supported by NIH/NIA R01AG056477. IZ is supported by the Robert-Koch-Institute through funds of Federal Ministry of Health (grant no. 1369-341) and DZNE (German Center for Neurodegenerative Diseases). KB reports consulting fees from Fujirebio Europe, IBL International, Roche Diagnostics. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. MB has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, and Servier. All other authors declare no competing interests. Ethics Approval Statement: Ethical clearance was obtained by the institutional review boards of all participating sites (European memory centers and ADNI Study sites) and all participants provided written, informed consent.