APOE Variant Directly Tied to Lewy Body Dementias in 2 Studies

APOE4 study

A variant of the apolipoprotein (APOE) protein, called APOE4, has been shown to directly affect Lewy body dementias, such as Parkinson’s disease.

Two separate studies, published simultaneously, found that APOE4 directly regulates levels of alpha-synuclein, which clumps  to form the nerve-damaging Lewy bodies that are the main culprits of the nerve cell death that defines Parkinson’s.

Their combined results help in understanding how APOE4 works, and how it affects disease progression. Greater insights into these mechanisms are vital for advancing research into treatments for Lewy body dementias.

Published in the peer-reviewed journal Science Translational Medicine, the two studies are “APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid,” and “APOE genotype regulates pathology and disease progression in synucleinopathy.”

“It’s nice when you do science separately … but reach similar conclusions,” Guojun Bu, PhD, senior author of one study and chair of neuroscience at the Mayo Clinic, said in a news release published in Neurology Today.

APOE4 has been the focus of research into both Alzheimer’s and Parkinson’s for some time. Studies have shown that it strongly associates with these diseases, and that it plays a strong functional role in the accumulation of amyloid-beta and tau within neurons.

Whether APOE4 directly promotes alpha-synuclein aggregation or affects disease progression as a result of these aggregates, however, is not known.

In each of these studies, scientists engineered mice to express one of three APO variants — E2, E3, or E4 — or to have no APOE at all (knockout mice). They then used different methods to examine associations between the APOE variants and disease features, or pathology.

Albert Davis, an assistant professor of neurology at Washington University School of Medicine in St. Louis and colleagues monitored one group of each type of mice, looking for the development of alpha-synuclein aggregates. His group injected groups of each of these engineered mice with alpha-synuclein fibrils to induce protein clumping, and see how its spread varied in each genetic background.

Among the first group, those expressing APOE4 (E4) showed higher amounts of insoluble and phosphorylated (pathologic) alpha-synuclein, and evidence of reactive gliosis — a type of neuroinflammation — than did mice in other groups.

Reactive gliosis refers to inflammation of glial cells, a class of protective neurons that include microglia, a cell often seen to be damaged in Parkinson’s. This inflammation typically occurs in response to damage to the central nervous system (CNS), such as the formation of Lewy bodies.

Mice carrying the E2 variant survived longer and did not show the motor difficulties seen in the other mouse groups.

Among mice injected with alpha-synuclein fibrils to monitor its spread throughout the brain, the E4 mice showed the greatest signs of pathology within the substantia nigra, the brain region most affected by alpha-synuclein aggregates in Parkinson’s.

This finding closely matched that of another recent paper, which concluded that microglia play “an integral role in the propagation and spread of alpha-synuclein pathology.”

The two papers reached different conclusions, however, regarding the order of events in inflammation and alpha-synuclein/Lewy body formation. While Davis’s group concluded that alpha-synuclein pathology leads to an inflammatory response, the other research group, lead by Jeffrey Kordower of Rush University, concluded that inflammation came first and played a driving role in alpha-synuclein aggregation.

“We and others in the field are going to look closely at that and follow up,” Davis said in the release.

Davis’ group also examined the genetic background of two groups of Parkinson’s patients, as a comparison to the mouse models. His group found people that in both cohorts, those with two copies of the E4 variant, showed the fastest cognitive declines.

“Our results demonstrate that APOE genotype directly regulates alpha-synuclein pathology independent of its established effects on [beta amyloid] and tau, corroborate the finding that APOE e4 exacerbates pathology, and suggest that APOE e2 may protect against alpha-synuclein aggregation and neurodegeneration in synucleinopathies,” these researchers concluded in their paper.

In the second study, led by Bu at the Mayo Clinic, mice were injected with viruses carrying different APOE variants.

Similar to Davis’ study, Bu’s group found that mice expressing E4, but not E2 or E3, showed more alpha-synuclein pathology and Parkinson’s-related symptoms, such as impaired behavior and the loss of neurons and synapses (the junctions between neurons where information is passed from one nerve cell to another). The E4 mice also showed deficits in their fat and energy metabolism.

Gu and his colleagues examined the brains of patients with Lewy body dementia, and discovered that those who had the APOE4 variant also showed greater alpha-synuclein pathology.

Eric Reimann, the executive director of Banner Alzheimer Institute, praised the studies, while adding that their results need to be confirmed in larger groups of both Parkinson’s patients, “including those without comorbid (simultaneously occurring) Alzheimer’s disease,” and healthy controls.

When two or more medical co-existing conditions can be common, telling the effects of one apart from the other is challenging. This is especially the case in disorders such as Parkinson’s and Alzheimer’s, which share many of the same disease features.

Reiman had also found the E4 variant to associate with higher odds for Lewy body dementia. In contrast to Davis’ study, however, Reiman found no link between the E2 variant and a lower disease risk.

Alice Chen-Plotkin, an associate professor of neurology at the University of Pennsylvania Perelman School of Medicine, commented in the release that “the data for E4 being bad is much stronger than for E2 being good.”

Although she expressed surprise at the strength of the effect Davis’s group found APOE4 to have on glial cells, she noted that researchers are coming to think much more about these nervous system support cells.

An ongoing Phase 2 clinical trial (NCT04154072), for instance, seeks to improve Parkinson’s outcomes by blocking glial activation and inflammatory signaling. At the same time, the National Institutes of Health (NIH) recently awarded a $4.8 million grant to study how APOE4 induces neurodegeneration.

The E2 variant is also the focus of an ongoing Phase 1 gene therapy trial (NCT03634007), seeking to deliver this protein to patients’ CNS as a way of treating Alzheimer’s disease.

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APOE Gene Variants Alter Alpha-synuclein Dynamics, Could Affect Dementia Occurrence in Parkinson’s, Study Suggests

APOE Gene Variants

Genetic variations in the gene apolipoprotein E (APOE) alter the dynamics of alpha-synuclein protein buildup in the brains of mice with Parkinson’s disease (PD), according to a new study. This suggests suggests that alterations in APOE could affect the occurrence of dementia in humans with the neurodegenerative disease, the researchers said.

Titled “APOE genotype regulates pathology and disease progression in synucleinopathy,” the study was published in Science Translational Medicine.

As many as 80% of people with PD will develop dementia — a group of symptoms affecting memory, thinking and social abilities — within two decades of being diagnosed. Nonetheless, the occurrence of dementia in Parkinson’s varies greatly person-to-person: “Many patients take years to develop dementia, whereas others have a more rapid course, and in some cases, dementia precedes motor symptoms,” the researchers said.

Parkinson’s is associated with the formation of toxic protein aggregates, or clumps, in the brain — particularly involving the protein alpha-synuclein. Alzheimer’s disease also is characterized by the accumulation of toxic protein aggregates in the brain, though the exact proteins involved are somewhat different.

The gene APOE encodes a protein of the same name, which helps form molecules called lipoproteins, which are responsible for packaging cholesterol and other fats and carrying them through the bloodstream.

A variant in this gene, called E4, is associated with a significantly increased risk of Alzheimer’s. APOE variants are known to affect how certain Alzheimer’s-associated proteins clump together in the brain. However, whether these variants also affect alpha-synuclein aggregation hasn’t been clear, nor has been the effect of variants in APOE on dementia in Parkinson’s.

Now, researchers at Washington University School of Medicine in St. Louis are trying to bridge this knowledge gap. Using mice with a form of alpha-synuclein prone to aggregation, the scientists engineered mice with one of three genetic variants in APOE — E2, E3, or E4 — or no APOE gene at all, called a knockout. They then compared alpha-synuclein in the brains of these mice.

Using multiple molecular assays, the researchers demonstrated that alpha-synuclein levels were significantly lower in mice with the E2 variant than in mice with the E4 variant or knockout mice. Animals with the E3 variant had alpha-synuclein levels in between these two extremes, though differences were generally not statistically significant in either direction.

Motor function and survival patterns followed trends consistent with this finding: E2 mice had higher motor scores, followed by E3, then E4, and knockout. Similarly, E2 mice survived significantly longer (median 18.4 months) than E4 (11.7 months) or knockout mice (11.6 months), with E3 mice in between the extremes (median 12.7 months).

These data suggest that APOE genetic variants affect the dynamics of alpha-synuclein in the brain.

“What really stood out is how much less affected the APOE2 mice were than the others,” Albert (Gus) Davis, MD, PhD, a professor at Washington University School of Medicine and the study’s lead author, said in a press release.

“It actually may have a protective effect, and we are investigating this now,” Davis said. “If we do find that APOE2 is protective, we might be able to use that information to design therapies to reduce the risk of dementia.”

The team then looked for connections between APOE variants and dementia in people with Parkinson’s.

First, the researchers assessed two groups of PD patients who had been followed for several years: one from the Parkinson’s Progression Markers Initiative, involving 251 people, and the other, which includes 170 people, from the Washington University Movement Disorders Center. In both groups, individuals with the E4 variant had significantly faster rates of decline in cognitive scores as compared with those with other variants. Importantly, this effect remained significant after adjustment for other factors known to affect cognitive decline, including the presence of neurotoxic proteins in the fluid around the brain, and educational attainment.

Additionally, in a separate group — the NeuroGenetics Research Consortium, numbering 1,030 people, in which cognitive scores were measured at only one time point — the E4 variant was associated with significantly lower cognitive scores at the time of assessment, and with the onset of cognitive difficulties at a younger age.

“Together, these data corroborate the finding that APOE ε4 is associated with cognitive impairment and a faster rate of cognitive decline in PD,” the researchers said.

Because this effect was independent of other toxic brain proteins, the team concluded this most likely was a consequence of increased alpha-synuclein in the brain, as evidenced by the data in mice.

All in all, these findings implicate APOE in the molecular progression of Parkinson’s and, specifically, the onset of dementia. Thus, APOE or related proteins in the brain might be a viable therapeutic target for treating dementia in Parkinson’s, the researchers said. Further studies will be needed to test this idea.

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