APOE4 Jacks Alzheimer’s Risk. This Gene Could Be an Antidote

By | May 28th, 2024

Scientists used genetic databases — and zebrafish brains — to probe the protective powers of a gene called FN1, which appeared to counteract the risk-rocketing affects of “Alzheimer’s gene” APOE4 and reduce Alzheimer’s risk by 70 percent.

While many genes can affect your risk of developing Alzheimer’s, most have a very small effect. The most common gene linked to late-onset Alzheimer’s disease is called apolipoprotein E (APOE), which moves cholesterol between the cells. The APOE4 variant is a well-known, significant risk factor for Alzheimer’s — carrying one copy increases the risk of developing the disease by 25 percent. With two copies, that risk goes up between three- and 12-fold. But one big question clouds the issue: Not everyone with the APOE4 gene develops Alzheimer’s disease. Is there something counteracting the influence of APOE4, protecting them?

Columbia University researchers sought to solve this mystery by scouring genetic databases for evidence of protective factors. They looked at thousands of profiles of healthy people over 70 who carried one or two copies of the gene, and lo, they all had one interesting, genetic feature in common: the presence of a gene variant that encodes for fibronectin, a component of the blood-brain barrier that controls the flow of waste and nutrients between the body and the brain.

Everyone carries two copies of the FN1 gene, one inherited from their mother and another from their father. There are different variants of the FN1 gene — each variant has a few small differences in the genetic code that makes up the gene. 

According to the study, between 1.85 percent and 3.33 percent of people with two copies of APOE4 also carried this potentially protective variant of a fibronectin gene (FN1) — around 1 in every 50 people who are E4 homozygous. For those who do, the variant (known as rs140926439) reduced the risk of developing Alzheimer’s by 70 percent, and in people with the variant who did develop Alzheimer’s, they tended to start experiencing symptoms an average of 3.4 years later than people without this FN1 variant.

Why? Here’s what researchers are seeing: In the brains of people with Alzheimer’s, a problematic protein called beta-amyloid forms clumps and kills off neurons. In an animal study, the research team saw that individuals who carried the FN1 variant appeared to have an easier time flushing beta-amyloid out, thanks to the work of the body’s janitor-like glymphatic system.

“These results gave us the idea that a therapy targeting fibronectin and mimicking the protective variant could provide a strong defense against the disease,” study co-lead Dr. Richard Mayeux said

How did the researchers find this protective variant?

The team looked across two genetic databases at more than 10,000 healthy, Alzheimer’s-free people over 70 who carried two copies of the APOE4 gene. They spotted that commonality of the rare mutation in a gene called FN1.  Then, they turned to an unexpected place to test its protective effects: the brains of zebrafish.

The team used the brain model of zebrafish — which share upwards of 70 percent of their DNA with humans — to figure out what this genetic variant does to protect against Alzheimer’s. They saw the variant reduces the amount of fibronectin that forms at the blood-brain barrier, and the researchers found that the fish with less fibronectin had an easier time flushing toxic plaques like beta-amyloid out of the brain naturally.

“It’s a classic case of too much of a good thing,” Caghan Kizil, an associate professor at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University, said in the press release. “It made us think that excess fibronectin could be preventing the clearance of amyloid deposits from the brain.”

Is there a way to tell if you have the protective variant of FN1? Most genetic tests like 23andMe look at specific parts of the genome and aren’t currently testing for this variant since it is so new. Some forms of genetic testing called whole genome sequencing provide a readout of every single gene and may be able to spot this variant. To avoid legal liability, some of these companies don’t analyze the data for you, meaning you’d need to do some extra work and use another tool to figure out if you have the gene or not. (That said, keep in mind that experts actually recommend against asymptomatic individuals getting tested for APOE4 or seeking out whole genome sequencing, for a few good reasons.)  

Helping the brain clear out amyloid

For people carrying the APOE4 gene, it’s now known that taking the existing amyloid plaque-clearing drug, Leqembi, may be risky: The APOE4 gene makes patients more likely to develop brain bleeds and swelling

Drugs targeting fibronectin could offer another tool for neurologists to help clear away amyloid plaques when monoclonal antibodies like Leqembi might be a no-go. According to the study’s authors, drugs targeting fibronectin could also work for people who don’t carry the APOE4 gene. 

“There’s a significant difference in fibronectin levels in the blood-brain barrier between cognitively healthy individuals and those with Alzheimer’s disease, independent of their APOE4 status,” Kizil said. “Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition.”

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2 thoughts on “APOE4 Jacks Alzheimer’s Risk. This Gene Could Be an Antidote

  1. I love learning about research into ways to defeat this condition and remove the damage caused by the presence of APOE4 gene(s).

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