The APOE Gene and Risk of Alzheimer’s

The e4 form of the APOE gene, referred to as APOE4, is the strongest genetic risk factor for developing Alzheimer’s disease in later life. A recent study suggests that that people with two copies of APOE4 are not just at risk for the disease, but are destined to develop it, in the same way that people with hereditary genetic mutations develop Alzheimer’s at younger ages. This conclusion is alarming and warrants a closer look.

doctor disclosing results_hands_cropped

By Alzheimer's Prevention Bulletin

30 years ago, researchers published the first paper on the association between the apolipoprotein E (APOE) gene and Alzheimer’s disease. Now, a recent paper published in Nature Medicine suggests that people with two copies of the APOE4 allele, also known as APOE4 homozygotes, are destined to develop the disease. Not all researchers agree with the study authors’ conclusions and the implications on how the disease is diagnosed and treated.

First, it is important to point out that the Nature Medicine study first looked for biological evidence of the disease, not whether a person had clinical symptoms or a diagnosis of the disease. To do this, they looked at whether fluid or brain imaging data from one time point (cross-sectional), showed evidence of elevated amyloid in the brain. They found that APOE4 homozygotes were more likely to have abnormal biomarker levels of amyloid than people with one or no copies of APOE4, with nearly all APOE4 homozygotes having elevated brain amyloid by age 80. Next, the authors examined the age at which memory problems appeared. As with prior studies, they found that on average, memory and thinking problems began around age 65 for people with 2 copies of APOE4, seven to 10 years earlier than APOE4 noncarriers.

Researchers from across the globe have commended the study authors for compiling data from such a large number of APOE4 homozygotes and point out the consistency with findings from other retrospective, case control studies. Many have raised the following points, suggesting that it is too soon to conclude that APOE4 homozygotes, like people with autosomal (familial) dominant genetic mutations and Down’s syndrome, are destined to develop Alzheimer’s.

  • Other studies have found that a sizeable percentage of APOE4 homozygotes between the ages of 60-75 do not meet criteria for elevated brain amyloid. APOE4 may raise a person’s risk for meeting biological criteria for the disease, but it is not a guarantee.
  • Longitudinal studies that enrolled APOE4 homozygote participants without memory and thinking problems and followed them over time have reported that those who remained unimpaired after age 75 have a lower risk of developing elevated brain amyloid, perhaps due to other unknown protective factors that make these individuals resistant to Alzheimer’s pathology.
  • Amyloid pathology is not sufficient for developing the disabling memory and thinking problems of Alzheimer’s disease dementia. In fact, a sizeable percentage of APOE4 homozygotes do not have evidence of tau pathology, the other pathological feature of Alzheimer’s in their brains. Tau is closely associated with memory and thinking problems, so these people may be resilient to Alzheimer’s dementia.
  • The Nature Medicine article primarily focused on data from non-Hispanic White individuals. Prior research has found that the risk of developing the disease among APOE4 carriers varies between different racial and ethnic groups. 

What are we to make of all of this? According to Jessica Langbaum, PhD, Senior Director, Research Strategy, Banner Alzheimer’s Institute “this study does not change how we would diagnose Alzheimer’s and certainly it is premature to say that someone with two copies of APOE4 will definitely develop Alzheimer’s. We need more research studies- like our Arizona APOE Cohort study- that enroll cognitively healthy people representing all APOE genotypes across races and ethnicities and follow them over time to understand risk and protective factors associated with the various APOE genotypes.” 

Clearly more research is needed to better understand the role APOE4 has in the risk of developing Alzheimer’s pathology in the brain (amyloid and tau) and the clinical symptoms of Alzheimer’s dementia. The Banner Alzheimer’s Institute is currently recruiting participants for its APOE cohort study. This study is open to cognitively healthy adults ages 50-90 from across the US and representing all six APOE genotypes, following them over time, to understand the risk and protective factors associated with each APOE result. To learn more about this study or browse other research studies looking for participants near you, please visit our Find a Study page.