Gene variant linked to Alzheimer's disease is a triple threat






Death sentence

Mouse brain nerve cells (green) making a disease-causing version of the tau protein were grown in lab dishes with supporting brain cells called glia. The glial cells produced different versions of the human APOE protein, or had no APOE. Glia making the APOE4 version of the protein often killed the nerve cells (bottom right).

In one experiment, mice that had no A-beta in their brains developed more tau tangles if they carried the human version of APOE4 than if they had the human APOE3 gene, Holtzman and colleagues found. That finding indicates APOE4 affects tau independently of A-beta.

Brains of people who died from various diseases caused by tangled tau had more dead and damaged cells if the people carried APOE4. The researchers also tracked 592 people who had low levels of A-beta in their cerebral spinal fluid — a clue that plaques have formed in the brain — and who showed symptoms of Alzheimer’s. Over a five- to 10-year period, the disease progressed 14 percent faster in people with one copy of APOE4 and 23 percent faster in people with two copies than in people who didn’t have that version of the gene, the researchers found. Those worsening symptoms are presumed to be caused by more rapid buildup of tau tangles in the APOE4 carriers.

APOE4 also seems to make Alzheimer’s worse by causing inflammation, the researchers found. Two kinds of mouse glial brain cells, microglia and astrocytes, making different versions of the APOE protein were grown with brain nerve cells, or neurons, that make disease-causing forms of tau. Mouse neurons grown with glia making no APOE grew well, even though they were making abnormal tau. But neurons grown with glia making APOE4 often died. APOE4 provoked inflammation responses in the normally friendly astrocytes and microglia, leading those cells to kill neurons, the researchers found. Such inflammation can make brain degeneration worse.

The data linking the APOE4 gene to tau tangles and brain inflammation is “super tight,” says molecular neurobiologist Sangram Sisodia of the University of Chicago. But the molecular details behind how APOE4 protein causes those effects are still vexingly absent, he says. Much more work is needed to uncover which molecules APOE4 interacts with, so that researchers can devise ways to counteract its negative effects in the brain.

Any therapies that decrease or eliminate APOE4 will need to be limited to the brain, because the protein is needed in the rest of the body to maintain healthy cholesterol levels, Vassar says. “You don’t want to give a person heart disease to cure Alzheimer’s disease.”

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