How exploiting a protective gene mutation might shield the brain from Alzheimer's disease

Despite the recent introduction of Biogen’s controversial Alzheimer's disease drug Aduhelm, the work on finding better treatments continues. To help with the search, scientists at the Mayo Clinic have shed light on how a genetic mutation might protect the brain from the neurodegenerative disorder.

A mutation in the APOE3 gene, dubbed APOE3-V236E, increases the formation of fatty molecules that are critical for nerve cell functioning and that may reduce the toxic aggregation of protein clumps in the brain, a Mayo Clinic team described in a study published in Science Translational Medicine.

The findings provide important insight into the mechanism of Alzheimer’s and other forms of dementia and could guide the development of effective strategies for treating some patients, the researchers said.

Back in 2014, a team led by the Mayo Clinic in Jacksonville, Florida, linked the rare APOE3-V236E variant with a reduced risk of Alzheimer’s. This time, some members of the same team set out to understand exactly how this mutation, now also called APOE3-Jac, protects against neurodegeneration.

RELATED: Alzheimer’s risk gene linked to post-chemotherapy cognitive decline

By studying brain tissues, the researchers found human brains carrying APOE3-V236E showed markedly reduced amounts of insoluble APOE protein, suggesting the variant might lower the propensity for protein aggregation. What’s more, brains with the variant either had a few diffused, shapeless beta-amyloid deposits—which are a hallmark of Alzheimer’s—or no plaque at all. Patients with other APOE3 variants, by contrast, had typical beta-amyloid plaques in their brains.

This finding showed that APOE self-aggregation might contribute to beta-amyloid deposition, the researchers concluded. Therefore, reduced APOE aggregation might be a critical mechanism for APOE3-V236E’s protective role against Alzheimer’s, they said.

APOE without fatty molecules tends to self-aggregate. The researchers wanted to understand how APOE3-V236E affects lipid metabolism, so they expressed the mutated gene in mice. Brain tissues from mice with APOE3-V236E showed increases in several classes of lipids that are critical for information processing and transmission between neurons, when compared to animals expressing non-mutated APOE3.

The researchers further tested their findings in a mouse model of Alzheimer’s. Amyloid deposition was weaker in animals expressing the genetic variant than in those expressing non-mutated APOE3, they found.

RELATED: A safer Alzheimer's drug than Biogen's aducanumab? Denali-WashU drug shows better profile in mice

Mice with APOE3- V236E had a significant reduction in clusters of immune cells called microglia around beta-amyloid plaques compared with those with APOE3, the Mayo team found. That's significant, because microglia normally work to clean up trash in cells, but as they do so, they can also cause inflammation that contributes to Alzheimer's. Animals with the variant also showed less plaque-associated neuritic dystrophy, which has been linked to cognitive decline in Alzheimer’s.

Many past Alzheimer’s studies have focused on the APOE4 gene, which is a well-known risk factor for the disease. As part of the new study, the Mayo scientists mutated APOE4 with V236E. Turns out, the APOE4-V236E variant showed reduced protein clumping.

All told, the study showed that the V236E variant on APOE3 and possibly other sites of APOE likely promotes healthy brain aging by reducing APOE self-aggregation, leading to decreased amyloid plaques and neuron toxicity, the researchers concluded. Drugs targeting APOE self-aggregation might reproduce this protective effect against Alzheimer’s, they said.