Apolipoprotein E4 is only a weak predictor of dementia and cognitive decline in the general population

Background: Apolipoprotein E (APOE) polymorphisms are unequivocally associated with risk for Alzheimer's disease (AD). It is crucial to understand how this genetic factor affects dementia risk in the general population, as well as in narrowly diagnosed, selected, patient groups. Methods: We assessed the cross sectional association between APOE genotype and dementia status in a community based sample, the MRC Cognitive Function and Ageing Study (MRC CFAS). In addition, we tested the effects of APOE genotypes on the differences in MMSE scores between the first and third assessment waves (about six years apart), an index of cognitive decline. Results: The APOE epsilon4 allele conferred increased risk for dementia (OR = 1.5, 95% CI = 1.1 to 2.2) compared to epsilon3 in the MRC CFAS sample. Compared with APOE epsilon3/epsilon3 subjects, those with the epsilon3/epsilon4 genotypes were not at significantly higher risk for dementia (OR = 1.1, 95% CI = 0.6 to 1.9), although epsilon4/epsilon4 subjects were (OR = 3.8, 95% CI = 1.0 to 14.0). Risk estimates were not different between men and women. Notably, our risk estimates for dementia were significantly lower than those reported for a diagnosis of Alzheimer's disease. MMSE scores at wave 3 and the difference in MMSE between baseline and at the third assessment wave were not different across APOE genotypes. Interpretation: The APOE epsilon4 allele is a weaker predictor for dementia in the general population than for AD. This may be because dementia can be caused by non-AD pathological processes and because most prevalent dementia occurs at an age when the APOE epsilon4 effect on AD risk (and therefore dementia) has started to decline.