APOE and dementia - resequencing and genotyping in 105,597 individuals

Introduction: The mechanism behind the strong association between the epsilon 2/epsilon 3/epsilon 4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well-characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia. Methods: The APOE gene was sequenced in 10,369 individuals, and nine amino acid-changing variants with frequencies >= 2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly. Results: Risk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 x 10(-4) and P = 1 x 10(-4) after APOE epsilon 2/epsilon 3/epsilon 4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus epsilon 33. Discussion: We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond epsilon 2/epsilon 3/epsilon 4. This underscores that dementia risk more likely relates to variants affecting levels of apoE.