APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease;: A case control study from central Norway

Background: The objective of this study was to analyze factors influencing the risk and timing of Alzheimer's disease (AD) in central Norway. The APOE epsilon 4 allele is the only consistently identified risk factor for late onset Alzheimer's disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (APOE) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the APOE epsilon 4 allele on the risk and the age at onset of AD in this population. Methods: 376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the APOE alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated. Results: Odds Ratio (OR) for developing AD was significantly increased in carriers of the APOE epsilon 4 allele compared to individuals with the APOE epsilon 3/epsilon 3 genotype. Individuals carrying APOE epsilon 4/epsilon 4 had OR of 12.9 for developing AD, while carriers of APOE epsilon 2/epsilon 4 and APOE epsilon 3/epsilon 4 had OR of 3.2 and 4.2 respectively. The effect of the APOE epsilon 4 allele was weaker with increasing age. Carrying the APOE epsilon 2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the APOE epsilon 4 allele, to 75.3 in carriers of one APOE epsilon 4 allele and 72.9 in carriers of two APOE epsilon 4 alleles. Age at onset in early onset AD (EOAD) was not influenced by APOE epsilon 4 alleles. Conclusion: APOE epsilon 4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.