Investigating the interplay between age and apolipoprotein E

Abstract

AbstractBackgroundAge is the major driver of dementia and aging is considered to be an independent, causal risk factor of dementia and Alzheimer’s disease (AD). We have examined whether the effect of age on dementia and AD is modified by genetic risk factors including the apolipoprotein E gene (APOE).MethodWe studied 204113 participants of the UK biobank who were over age 37 years at baseline (mean 64 years, SD=2.85) and were followed up with for dementia over time (mean 10.2 years). The study is based on 4,578 patients with dementia, including 1,741 with Alzheimer disease. We investigated whether APOE and other genes implicated in dementia modified the effect of age on dementia and AD. To study the effect of the other genes, a genetic risk score (GRS) was constructed for the genes other than APOE based on Bellenguez et al. Those in the highest and lowest quintile were compared across four APOE genotype groups (APOE22/23, APOE33, APOE34/APOE24, and APOE44).ResultThe effect of age on the risk in all dementia and AD differed significantly between carriers of the APOE44 and APOE24/34 and non‐APOE*4 carrier (APOE33 and APOE22/23) groups. Within the APOE44 genotype, the effect of age on the risk of dementia also differed significantly between those in the highest and lowest quintile of the GRS. In APOE24/34 carriers, a similar pattern was seen. In APOE22/23 carriers, we found that the association between age and dementia and AD does not differ between those in highest and lowest quintile of the GRS.ConclusionIn UK Biobank, the association between age and the risk of dementia and AD is modified by APOE genotype and other genetic risk factors. Our data show that calendar age by itself is not a sufficient cause of dementia or AD but that the effect of age is conditional of the person’s APOE genotype and other genetic risk factors.Bellenguez C, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022 Apr;54(4):412‐436. doi: 10.1038/s41588‐022‐01024‐z.