Serum apolipoprotein E is associated with long-term risk of Alzheimer's disease: The Rotterdam Study

Background: Serum levels of apolipoprotein E (apoE) have been suggested as potential biomarker for dementia, but the long-term association between apoE and risk of dementia is uncertain. Methods: Between 1990 and 1993, we measured serum apoE by immunoassay in 1042 non-demented individuals (mean ± SD age 68.4 ± 7.3 years; 59.3% women) from the population-based Rotterdam Study. Follow-up for dementia was complete until 2014. We used Cox models to determine the risk of dementia and Alzheimer's disease in relation to apoE, adjusting for age, sex, educational level, cardiovascular risk factors, and additionally APOE genotype. Results: Serum apoE was associated to APOE genotype (p-trend = 1.0E-51, r2 = 0.21). In men, apoE tended to be lower with age, whereas in women the opposite was observed (p-trend = 0.07 and 0.08, respectively). During a median follow-up of 15.7 years (IQR 9.7-21.7), 220 participants developed dementia, of whom 180 had Alzheimer's disease. Lower serum apoE was associated with an increased risk of dementia (HR, 95%CI, per SD decrease: 1.25, 1.05-1.48) and in particular Alzheimer's disease (1.51, 1.23-1.86), which remained statistically significant for Alzheimer's disease after additionally adjusting for APOE genotype (1.28, 1.01-1.62). When stratifying analyses in 5-year time frames, risk estimates were similar throughout the study period. Serum apoE tended to marginally improve 20-year prediction of Alzheimer's disease (IDI 0.008, 95%CI -0.001-0.026, p = 0.086), but not all dementia. Conclusion: Serum apoE is associated with long-term risk of Alzheimer's disease in the general population, independent of APOE genotype. Additional predictive value of serum apoE was limited.

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