On 3 February, Dr Eric Reiman and colleagues published a paper in Nature Communications, showing that people with two copies of the APOE2 allele have a substantially lower risk of developing Alzheimer’s dementia (AD) compared to people with two copies of APOE4.
We each possess two copies (or “alleles”) of the APOE gene, of which there are three different variants: APOE2, APOE3 and APOE4. The combination of APOE alleles we possess determines our APOE “genotype” - for example, E2/E2, E2/E4 or E4/E4. In 1993, a landmark study showed that individuals with two copies of APOE4 (named APOE4 “homozygotes”) were at much higher risk of developing AD at a younger age. Conversely, the APOE2 variant appeared to be neuroprotective, reducing the risk of developing AD. Of the three APOE variants, APOE4 has attracted the most attention. Much less is known about APOE2, in part due to the fact that it is the least common of the three variants: 78% of people have at least one APOE3 allele, compared to only 8% for APOE2. Based on these numbers, only 0.64% of the population are likely to carry two APOE2 alleles. This means that to fully understand the risk benefit of APOE2, studies must incorporate thousands of participants in order to have a sufficiently large number of APOE2 homozygotes to study. Moreover, many studies do not include neuropathological (ie autopsy) assessment of AD, arguably the most definitive and reliable way to diagnose AD. As a result, the impact of APOE genotype on AD may have been underestimated.
To address this methodological issue, and to dissect the risk contribution of the different APOE variants, Dr Reiman and colleagues decided to study the Alzheimer’s Disease Genetics Consortium (ADGC) cohort. The ADGC cohort includes brain autopsy samples and clinical data from 4018 participants with neuropathologically-confirmed AD alongside 989 unaffected controls. The wider ADGC cohort includes clinical data from 10,430 probable AD cases and 13,426 unaffected controls.
Confirming the results of previous studies, the researchers found that each additional copy of APOE4 confers a substantially higher risk of AD; participants with two APOE2 alleles had 99.6% lower risk of developing AD compared to those with two APOE4 alleles. Interestingly, the odds ratios (measuring the likelihood of an association between APOE genotype and AD) for the neuropathologically confirmed group were slightly different to the odds ratios for the group of participants without neuropathological confirmation. In the neuropathologically-confirmed group, people with two APOE4 alleles had an odds ratio of 31.2 (i.e they were 31 times more likely to have AD compared to APOE3 homozygotes), versus to an odds ratio of 10.7 in the group without neuropathological confirmation. At the other end of the scale, people with two copies of APOE2 had an odds ratio of 0.13 (i.e they are ~90% less likely to develop AD compared to APOE3 homozygotes), compared to an odds ratio of 0.52 for APOE2 homozygotes without neuropathological confirmation. The protective effect of APOE2 extended to Tau pathology in the brain, with APOE2 homozygotes having far fewer neurofibrillary tau tangles compared to all other genotypes.
Together, these results show that the possession of two APOE2 alleles confers an even larger protective effect against the development of AD than previously estimated, confirming that the opposite is true for APOE4. Further studies with neuropathological confirmation are now required to clarify the impact of the different APOE genotypes on AD, incorporating larger numbers of APOE2 homozygotes from different ethnic groups and socioeconomic backgrounds. Link to article: https://www.nature.com/articles/s41467-019-14279-8