Scientists May Have Finally Uncovered The Alzheimer’s ‘Trigger’

Despite millions invested in treating and combating the disease, Alzheimer’s is poised to affect an estimated 16 million American seniors by 2050.

Scientists have recently made huge strides in understanding environmental risk factors related to Alzheimer’s and developing new detection techniques. But lowering rates of the disease will take a deeper understanding of how Alzheimer’s alters the human brain at a chemical, genetic level. With that knowledge, scientists can develop therapies to prevent, fight, or reverse damaging effects.

To that end, researchers may have uncovered a new piece to the Alzheimer’s puzzle: A team from Washington University in St. Louis recently determined how a specific gene variant called ApoE4 – a cholesterol-carrying chemical that is a known risk factor for Alzheimer’s – exacerbates neurological damage when exposed to a certain “trigger” protein in the brain.

By reducing levels of ApoE4, the researchers believe they “may be able to stop the disease process.”

Since around 1993, scientists have known that the presence of the ApoE4 gene variant (or “allele”) amplifies an individual’s risk of developing Alzheimer’s. The allele, found in 10-15% of people, can make someone up to 12 times more likely to develop the disease.

Working from that knowledge, researchers have tried to determine why ApoE4 is so damaging ever since. Most efforts have focused on understanding ApoE4’s relationship to the beta-amyloid peptide, which plays a significant role in the development of Alzheimer’s. As the disease advances in the brain, pieces of the β-amyloid protein – which are chemically “sticky” –  clump together. Over time, the clumps accumulate into the “plaques” that are a hallmark of Alzheimer’s.

β-amyloid clumps accumulate in the brain when ApoE4 is present. But while the amyloid clumps themselves are characteristic of all Alzheimer’s cases (and are detectable on brain scans), they don’t actually kill brain cells, nor cause symptoms such as memory loss and confusion.

But β-amyloid is not the only chemical that contributes to Alzheimer’s development in the brain. Another protein, tau, also misbehaves in Alzheimer’s-afflicted brains: In healthy people, tau stabilizes nerve cell structure (and helps maintain normal brain function); in Alzheimer’s patients, however, tau becomes toxic – accumulating into a different set of tangled clumps (distinct from β-amyloid protein clumps) that are another hallmark of the disease.

Since the brains of Alzheimer’s patients exhibit both amyloid plaques and intracellular tau tangles, some scientists have called the two proteins the “the trigger and bullet” in Alzheimer’s disease pathogenesis. The plaques and tangles develop separately in the brain, but essentially collude to cause neurological damage: Studies have shown that the presence of toxic tau likely enhances the toxicity of β-amyloid – triggering β-amyloid plaque to cause neurological damage.

With their new study, the Washington University researchers shifted their focus from amyloid “bullets” to the tau-tangle “triggers.” The team investigated how ApoE4 interacts with tau – finding that ApoE4 worsens the brain damage caused by tau tangles.

More importantly, they found that in the absence of the ApoE4 allele the tau protein tangles did very little to harm brain cells.

That finding is especially significant because the ApoE gene (which can include the allele variant ApoE4), which transports cholesterol around the body, is not present in 100% of people; the small number of individuals who lack a functional ApoE gene have very high cholesterol levels (and often die young, with cardiovascular problems) but do not experience problems in the brain.

Because of that, the research suggests that decreasing ApoE levels specifically in the brain could minimize, slow, or block neurodegeneration – even in people who are already accumulating tau tangles:

“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,” said David Holtzman, MD, the study’s senior author.

Holtzman and colleagues arrived at their findings after conducting tests on genetically modified mice carrying a mutant form of human tau that is prone to forming toxic tangles. The mice (which all lacked the mouse version of the ApoE gene) were also modified to carry one of the three variants of the human ApoE gene: ApoE2, ApoE3 or ApoE4.

By the time they were nine months old, all ApoE-carrying mice had widespread brain damage (which none of the control mice, which lacked ApoE entirely, exhibited). The ApoE4 mice exhibited the most drastic neurodegeneration of the data set.

It also appeared that the presence of ApoE4 caused the immune cells of mice carrying the allele to “turn on” a set of genes that can trigger inflammation and kill neurons en masse. (Immune cells from mice lacking ApoE were barely activated.)

“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.

To compare their findings in mice against the affects of ApoE and tau in people, the researchers examined autopsy samples from 79 people who had died from so-called “tauopathies” other than Alzheimer’s disease in the past 10 years. (Tauopathies are the class of neurodegenerative diseases associated with the aggregation of tau protein.)

Noting the different ApoE variants present in the deceased, they found that people with ApoE4 had more brain damage at the time of death than those that lacked ApoE4.

The findings demand further study, but are a significant contribution to the body of work on Alzheimer’s disease. (One factor that makes the research especially notable is the involvement of Holtzman, who had previously focused his research on the link between ApoE4 and β-amyloid as key to Alzheimer’s, according to reports.)

And while unpacking the relationship between tau and β-amyloid will continue to drive research work for years to come, greater understanding of the ApoE gene’s impact on the brain could prove seminal to ultimately developing a cure for Alzheimer’s.

“All forms of ApoE — even ApoE2 — are harmful to some extent when tau is aggregating and accumulating,” said Holtzman. “The best thing seems to be in this setting to have no ApoE at all in the brain.”

The original study “ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy” was published in the journal Nature in September 2017. Full information is available here.