Science magazine article on ApoE4 research

[NF52]

The Burden of a Gene: Can new insights into its function help stave off disease? was published by Science magazine online today. It arose from a request in April to TheresaB, Board Member, for contacts with ApoE 4/4 who were in the AHEAD study. ChicagoGirl, whose topic AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401) has been viewed an impressive 338, 074 times, was interviewed for the story, but not included in the final piece due to space constraints. Deep thanks to

and Carol Turner and her brother Ray Smith for helping to spread the word about the importance of ApoE4-focused research!

In my view, this is a compelling story and a careful discussion of how ApoE 4 came to be recognized as having significant risks for late-life sporadic Alzheimer's. Ms. Kaiser interviewed ApoE4-focused researchers such as Dr. Yadong Huang and others on new promising lines of research for ApoE 4 carriers. She herself has ApoE 3/4 and provides a link to this forum, as well as recommendations from clinicians for lifestyle interventions.

Below are a few excerpts:

Last year, National Institute on Aging Director Richard Hodes and former National Institutes of Health (NIH) Director Francis Collins asked a working group of APOE4 researchers to review the latest evidence.
One clue came from large studies of Alzheimer’s in African Americans led by Jeffery Vance of the University of Miami, who is Pericak-Vance’s husband. His team found that people who inherited APOE4 from African ancestors have differences in surrounding DNA that lower the gene’s expression in brain cells compared with those who got it from European ancestors. That could explain why African American APOE4 carriers don’t face as high a risk of Alzheimer’s as white carriers.

Another study out this year led by neurologist Michael Greicius at Stanford University found two non-Hispanic white individuals with one copy of APOE4 who remained dementia and amyloid free at ages 76 and 90, apparently because of mutations that disabled the variant—more evidence that reducing ApoE4 may be helpful.
...
[At MIT] Tsai’s group is exploring whether a cocktail of already approved drugs or supplements could thwart some of the APOE4 damage her group has observed. The team has reported, for example, that the nutrient choline can correct lipid processing in cultured human astrocytes with APOE4. In a small trial in Texas, Tsai’s collaborators are testing the effects of choline supplements on lipid profiles in spinal fluid of cognitively normal people with at least one copy of APOE4.

It’s “a small step toward fulfilling our idea of an affordable, accessible, safe way to move the needle for carriers,” Tsai says.

[Julie G]

Thanks, NF52! This is a nice review of ApoE4 research. Members of our community have previously met with Drs. Robert Mahley and Yadong Huang (cited in the article) to learn about their small structure corrector which, sadly, hasn't panned out.

Some of the statements, characterizing ApoE4 as "toxic," are hard to believe from an evolutionary perspective. I wholeheartedly agree with Dr. Hussein Yassine, who points out that carrying APOE4 isn’t inherently a defect.

The variant may actually be the original form of the gene—the one our early human ancestors had—and could in fact offer advantages. “There is a reason why so many people have it,” he says. Some studies have proposed APOE4 helps carriers fight off childhood pathogens. Other research even suggests young adults with APOE4 have better spatial memory and other subtle cognitive advantages.

You can hear a podcast that Dr. Yassine did for our community: ApoE4 Mechanisms that Lead to Disease: Optimizing for Neuro-Resilience

Finally, while the Lexeo Therapeutics therapies have largely proven safe, they haven't improved cognition — to my knowledge. The addition of the Christchurch gene with E2 to be injected into the CSF of E4 carriers is exciting and another one to watch.