Researchers Identify Role of ApoE4 Gene as Possible Drug Target in Alzheimer’s Disease

Researchers have long known that people with the ApoE4 gene variant have a higher risk of developing Alzheimer’s disease, compared to the general population. However, it was previously unknown how this allele contributed to the pathology and symptoms of this form of dementia, until now.

A team of neurology researchers at Washington University School of Medicine in St. Louis have found that in the presence of the ApoE4 protein, another protein known as tau forms tangles in the brain which contributes to neuronal damage characteristic of Alzheimer’s disease. When the investigators looked at the effect of tau tangles in the absence of ApoE4, they found that they were not as harmful to brain cells.

The researchers published their findings in the journal, Nature.

While previous efforts to develop a therapy for Alzheimer’s disease have focused on targeting the accumulation of beta amyloid plaques, research suggests that these protein accumulations are not the cause of Alzheimer’s pathology. In light of the newly-uncovered role of ApoE4, drug discovery efforts may focus on using this variant as a target.

“Once tau accumulates, the brain degenerates,” said Dr. David Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “What we found was that when ApoE is there, it amplifies the toxic function of tau, which means that if we can reduce ApoE levels we may be able to stop the disease process.”

In their study, Holtzman and his colleagues used four different varieties of genetically modified mice, all of which were developed to express a form of human tau protein which was more susceptible to forming tangles in the brain. The mice also expressed one of three human ApoE gene variants: ApoE2, ApoE3 or ApoE4. A fourth variety of mice lacked the ApoE gene altogether.

The ApoE3 variant is the most common of the three, while the ApoE4 mutation is associated with an up to 12-fold increased risk of developing Alzheimer’s disease. Interestingly, people carrying the ApoE2 allele appear to be protected from developing dementia.

Once the mice reached nine months of age – a stage of life that corresponds to middle age in humans – their brains were analyzed for signs of damage. Mice carrying the ApoE4 variant showed the most advanced neurodegeneration, with memory centers like the hippocampus and entorhinal cortex appearing to be markedly shrunken.

ApoE4 mice also showed a stronger immune and inflammatory response in the brain, compared to the other varieties of mice. In contrast, mice expressing ApoE2 showed little brain damage compared to the other variants, and mice lacking the ApoE gene altogether exhibited next to no neurodegeneration.

“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,” said Holtzman. “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.”

Despite these findings, completely blocking the action of the ApoE protein is unlikely to be a successful strategy for treating, or even preventing, Alzheimer’s disease; the protein plays a vital role in moving cholesterol throughout the body. A small number of people around the world have a rare disease in which they lack a functional ApoE gene. While these individuals show no cognitive impairment, they do suffer from high cholesterol which can lead to potentially-fatal cardiovascular disease if left untreated.

Instead, the researchers suggest that drugs designed to selectively block ApoE expression in the brain may be able to slow the accumulation of tau tangles and associated neurodegeneration. While previous efforts have focused on targeting amyloid beta or tau to treat Alzheimer’s, Holtzman says that ApoE4 has not previously been considered as a drug target.

“Assuming that our findings are replicated by others, I think that reducing ApoE in the brain in people who are in the earliest stages of disease could prevent further neurodegeneration,” Holtzman said.