Scientists are coming closer to understanding how the gene variant apolipoprotein E4 (ApoE4) raises the risk of Alzheimer’s disease.
Blocking ApoE4 — one of several variants of the ApoE gene — in the brain may prevent cell death and inflammation and lead to a treatment for Alzheimer’s, concludes a study, “ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy,” that appeared in the journal Nature.
Experts have long recognized that ApoE4 increases Alzheimer’s risk but didn’t know why. Their research has also focused on the presence of a protein called tau, which forms clumps in the brains of people with Alzheimer’s and other neurodegenerative diseases.
Tau is slightly toxic to brain cells, but ApoE4 aggravates that toxicity in mice, researchers at Washington University School of Medicine in St. Louis, Missouri, found in this study. The laboratory mice they used had toxic Tau tangles in their brains, but had either no human ApoE gene, or had one of the human gene variants ApoE2, ApoE3 and ApoE4.
At nine months of age, the mice carrying the gene variants showed extensive brain damage. Mice carrying ApoE4 had the most damage, and those carrying ApoE2 had the least. Mice lacking the gene altogether displayed almost no brain damage at all. In addition, ApoE4 mice had inflammation caused by the immune system — unlike the mice carrying the other ApoE variants.
“ApoE4 seems to be causing more damage than the other variants because it is instigating a much higher inflammatory response, and it is likely the inflammation that is causing injury,” Dr. David Holtzman, the study’s senior author, said in a press release. “But all forms of ApoE – even ApoE2 – are harmful to some extent when tau is aggregating and accumulating. The best thing seems to be in this setting to have no ApoE at all in the brain.”
To get an idea of whether the results seen in experiments in mice also hold true for people, researchers studied the brains of 79 people who had died from other diseases caused by tau. People with ApoE4 had more damage than those without it.
ApoE transports cholesterol throughout the body, and is therefore essential. However, its absence in the brain alone may not be harmful, because people who lack the protein altogether appear to have normal brain function.
Holtzman says targeting ApoE has not yet been tried as a potential therapy for Alzheimer’s.
“Assuming that our findings are replicated by others,” he said, “I think that reducing ApoE in the brain in people who are in the earliest stages of disease could prevent further neurodegeneration.”