We read with interest the article by Hayden et al,1 which suggested that the apolipoprotein E (APOE) ϵ4 allele was not associated with global cognitive decline in the absence of latent Alzheimer disease (AD). Indeed, we have previously investigated in the Kungsholmen Project the relation of the APOE ϵ4 allele to global cognitive decline, taking into account incident dementia diagnosed at the end of follow-up.2 We found that the APOE ϵ4 allele was significantly associated with global cognitive decline with progression to dementia, and to AD in particular, whereas the association with cognitive decline without progression to dementia was less evident. Although Hayden et al argued that the residual cognitive decline related to APOE ϵ4 was unlikely owing to unidentified incident AD cases, it is possible that the residual decline can be a part of the early process of future development of the disease. In addition, because in both studies the participants were cognitively normal or free of dementia at baseline and there was an approximately 3- to 4-year interval between cognitive assessments, the remarkable association between APOE ϵ4 allele and dementia-related cognitive decline implies that carriers of APOE ϵ4 allele are likely to progress more quickly than noncarriers from normal cognition to evident syndrome of dementia.2 Given the similar findings from 2 independent, well-characterized cohort studies1,2 and others,3,4 we conclude with more confidence that the APOE ϵ4 allele is mainly associated with cognitive decline due to incipient AD and that the inconsistent findings of APOE ϵ4 allele related to cognitive decline in the literature are largely owing to whether incipient or prodromal AD or dementia cases are included in the analytical sample.
Qiu C, Fratiglioni L. Apolipoprotein E ϵ4 Status and Cognitive Decline With and Without Dementia. Arch Neurol. 2010;67(8):1036-1037. doi:10.1001/archneurol.2010.163