In a recent study we showed that the ɛ4 variant of APOE, the single most important gene for cognitive aging, was associated with dementia risk in 1453 elderly participants of the Helsinki Birth Cohort Study (HBCS), whereas regulatory variants linked with the transcriptional activity of the gene known as rs405509 and rs440446 was not. The study by Rantalainen et al is currently in press in Neurobiology of Aging.
The APOE gene has three common variants or isoforms, ɛ2, ɛ3 and ɛ4, which code for different variants of apolipoprotein E (apoE). The apoE protein performs multiple key functions in the central nervous system, and the ɛ4 isoform of the gene produces a functionally deficient form of the protein. The ɛ4 isoform of the gene has been found in numerous studies to be associated with a higher risk of dementia and Alzheimer’s disease (AD), and it has also been linked with lower performance in measures of normal cognitive functioning particularly in old age.
Other variants in the APOE gene have also been associated with the risk of dementia and AD. These include single-nucleotide polymorphisms that are involved in the regulation the gene’s activity of RNA transcription leading to production of the apoE protein. However, these associations have varied between studies according to the age and ethnicity of the study participants, and studies on the associations between these variants and normal cognitive functioning have been extremely scarce.
Our results replicate the well-documented finding regarding the dementia risk factor status of APOE ɛ4 in the HBCS cohort. Importantly, the new study complements a study published in the same journal in 2016 in which we found that the rs405509 and rs440446 regulatory variants were associated with cognitive ability in old age and with aging-related cognitive change, but the protein-coding ɛ4 isoform was not. Together these findings from a single study cohort suggest that in the HBCS the APOE gene may be associated with dementia and AD risk and aging-related cognitive change via at least partially distinct mechanisms: a protein isoform-dependent mechanism associated with risk of dementia and AD, and an isoform-independent mechanism associated with aging-related cognitive change.