Finding That APOE4 Is Toxic in Alzheimer’s Can Help Guide Targeted Therapies

A working group of senior investigators, convened by the Alzheimer’s Disease Sequencing Project (ADSP), has reached a consensus that the APOE4 gene, long debated in Alzheimer’s research, is definitively toxic. This breakthrough not only opens the door for targeted therapies but also underscores the gene’s varying risk levels across different populations.

In this exclusive MedPage Today video, Jeffery Vance, MD, PhD, of the University of Miami Miller School of Medicine, describes the findings from the data analysis and how they might significantly reshape the future of Alzheimer’s treatment strategies.

Following is a transcript of his remarks:

APOE4 is the strongest genetic risk factor for Alzheimer’s disease by far. And it’s been known for the last 31 years.

About anywhere from 40% to 60% of Alzheimer’s patients have an APOE4 [allele], depending on which study you looked at. So, we’ll say 50%. It hasn’t really been a therapeutic target for all these years. And one of the questions has been whether the risk for Alzheimer’s disease is due to having not enough of APOE — in other words APOE4 is not functional enough — or whether it’s toxic. So this question came up, and Francis Collins and Dr. Hodes of the NIA — National Institute on Aging — asked the ADSP to form this working group of senior investigators. And we went through all the data. And the end point is APOE4 is toxic, the data are overwhelming, and it was a consensus report.

And this is important because it’s really opened up therapeutic endeavors to target APOE4 as a therapeutic target for Alzheimer’s disease. And the interesting thing about APOE4 is that the risk for APOE4 is different among different populations.

It’s been known for quite a while that Alzheimer’s patients from African and African American populations have less risk for Alzheimer’s disease from the same gene than Europeans and Asians. And it really wasn’t known until 2018, our group showed that it was due to what’s called local ancestry around the APOE4 gene.

This local ancestry idea is important because African Americans and American Hispanics or Latinos are admixed individuals. So they have multiple ancestries, their background, right? And that means that if you have an APOE4 gene, your risk — and if you’re from those populations — can vary quite a bit depending on where you inherited that APOE4 from. So if you inherited it from your European ancestor, you have the European risk. But if you inherited it from your African ancestor, you have the African risk. And you can’t tell that by just looking at somebody.

So there are a lot of different approaches that are now being taken by different groups to try to lower the expression or the protein of APOE4 as a therapy.